Copper in Glucose Intolerance, Cognitive Decline, and Alzheimer Disease.

Trace metal dyshomeostasis has been linked to loss of cognitive performance. In particular, a disturbance in the regulation of copper (Cu), characterized by an increase in circulating Cu not bound to ceruloplasmin (non-Cp Cu), is thought to play a role in the development of Alzheimer disease (AD) and other neurodegenerative diseases in the aging population. Non-Cp Cu is redox active and its toxicity is thought to result from its ability to accelerate oxidative stress and advanced glycation endproduct (AGE) formation, leading to extracellular matrix damage in tissues including the brain. Cognitive loss is increasingly recognized to be a feature of type 2 diabetes and the increased AGE formation characteristic of diabetes may play a role in the development of this complication. There also is evidence for copper dyshomeostasis in type 2 diabetes, and therefore this could contribute to the cognitive deterioration associated with this disease. Demonstrating that disturbances of copper homeostasis correlate with an increased rate of cognitive decline in type 2 diabetes patients, and that they correlate with an increased rate of conversion from prediabetes to diabetes would bring almost immediate benefits in the clinical community in terms of treatment efficacy, AD prevention, and cost savings.

Intrathecal administration of a novel apoE-derived therapeutic peptide improves outcome following perinatal hypoxic-ischemic injury.

Perinatal hypoxic-ischemic brain injury remains a significant clinical problem for which there remains no adequate therapeutic intervention. Apolipoprotein E (apoE) is a 299 amino acid protein that has been demonstrated to modify functional recovery following acute ischemic and traumatic brain injury. The aim of the current study was to evaluate whether administration of an apoE-derived peptide could reduce CNS injury in a rodent model of perinatal hypoxia and ischemia. We found that intrathecal delivery of an apoE-mimetic peptide caused a significant reduction in post-ischemic brain necrosis, as reflected by decreased reduction in ipsilateral brain weight 7 days following hypoxic-ischemic injury. These results suggest that administration of an apoE-derived therapeutic peptide represents a novel therapeutic strategy in the clinical setting of perinatal hypoxic-ischemic injury.

Serum levels of soluble receptor for advanced glycation end-products and metabolic syndrome: the Northern Manhattan Study.

OBJECTIVE: Recent studies have shown a strong link between serum soluble receptor for advanced glycation end-products (sRAGE) levels and cardiovascular risk factors and disease. What is less clear is the relationship between metabolic risk factors and sRAGE levels. Here, we tested the hypothesis that lower sRAGE levels may be associated with the metabolic syndrome (MetS) in an urban multi ethnic population. MATERIALS/METHODS: From the Northern Manhattan Study (NOMAS), we included 1101 stroke-free participants (mean age: 71 ± 9 years, 60% women, 64% Hispanic, 18% black, 16% white). Serum sRAGE was measured by ELISA. Quantile regression analysis was performed to evaluate the association between sRAGE and MetS components and MetS, after adjusting for sociodemographics, smoking status and kidney function. RESULTS: The median (interquartile) sRAGE was 899 pg/ml (647-1248 pg/ml), 42% had metabolic syndrome. The prevalence of unfavorable metabolic factors was 50% for waist circumference (WC), 81% for blood pressure, 39% for fasting glucose, 35% for reduced high density lipoproteins (HDL), and 23% for triglycerides. After adjustment, the median sRAGE levels were at least 120 pg/ml lower in those who had elevated WC (p<0.0001), blood pressure (p=0.0014), and fasting glucose (p<0.0001), and those who had 2 or more unfavorable metabolic factors. No relationship was seen between sRAGE levels and elevated triglycerides or reduced HDL levels. Interaction and stratified analyses revealed that the association of sRAGE with MetS was more prominent in Hispanics compared to whites, and displaying no association with components of MetS in blacks. CONCLUSIONS: sRAGE levels were mainly associated with MetS factors related to obesity, diabetes and hypertension, and displayed variation with ethnicity in a multi-ethnic population. Further studies of sRAGE, MetS and their relationship to cardiovascular disease are warranted.

Characterization of circulating endothelial cells in acute myocardial infarction.

Acute myocardial infarction (MI), which involves the rupture of existing atheromatous plaque, remains highly unpredictable despite recent advances in the diagnosis and treatment of coronary artery disease. Accordingly, a clinical measurement that can predict an impending MI is desperately needed. Here, we characterize circulating endothelial cells (CECs) using an automated and clinically feasible CEC three-channel fluorescence microscopy assay in 50 consecutive patients with ST-segment elevation MI and 44 consecutive healthy controls. CEC counts were significantly elevated in MI cases versus controls, with median numbers of 19 and 4 cells/ml, respectively (P = 1.1 × 10(-10)). A receiver-operating characteristic (ROC) curve analysis demonstrated an area under the ROC curve of 0.95, suggesting near-dichotomization of MI cases versus controls. We observed no correlation between CECs and typical markers of myocardial necrosis (ρ = 0.02, creatine kinase-myocardial band; ρ = -0.03, troponin). Morphological analysis of the microscopy images of CECs revealed a 2.5-fold increase (P < 0.0001) in cellular area and a twofold increase (P < 0.0001) in nuclear area of MI CECs versus healthy controls, age-matched CECs, as well as CECs obtained from patients with preexisting peripheral vascular disease. The distribution of CEC images that contained from 2 to 10 nuclei demonstrates that MI patients were the only subject group to contain more than 3 nuclei per image, indicating that multicellular and multinuclear clusters are specific for acute MI. These data indicate that CEC counts may serve as a promising clinical measure for the prediction of atherosclerotic plaque rupture events.

Identification of novel potent bicyclic peptide deformylase inhibitors.

Screening of our compound collection using Staphylococcus aureus Ni-Peptide deformylase (PDF) afforded a very potent PDF inhibitor with an IC(50) in the low nanomolar range but with poor antibacterial activity (MIC). Three-dimensional structural information obtained from Pseudomonas aeruginosa Ni-PDF complexed with the inhibitor suggested the synthesis of a variety of analogues that would maintain high binding affinity while attempting to improve antibacterial activity. Many of the compounds synthesized proved to be excellent PDF-Ni inhibitors and some showed increased antibacterial activity in selected strains.