Medical Biology - Research Publications

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    Significant Accumulation of Polymyxin in Single Renal Tubular Cells: A Medicinal Chemistry and Triple Correlative Microscopy Approach
    Azad, MAK ; Roberts, KD ; Yu, HH ; Liu, B ; Schofield, AV ; James, SA ; Howard, DL ; Nation, RL ; Rogers, K ; de Jonge, MD ; Thompson, PE ; Fu, J ; Velkov, T ; Li, J (AMER CHEMICAL SOC, 2015-02-03)
    Polymyxin is the last-line therapy against Gram-negative 'superbugs'; however, dose-limiting nephrotoxicity can occur in up to 60% of patients after intravenous administration. Understanding the accumulation and concentration of polymyxin within renal tubular cells is essential for the development of novel strategies to ameliorate its nephrotoxicity and to develop safer, new polymyxins. We designed and synthesized a novel dual-modality iodine-labeled fluorescent probe for quantitative mapping of polymyxin in kidney proximal tubular cells. Measured by synchrotron X-ray fluorescence microscopy, polymyxin concentrations in single rat (NRK-52E) and human (HK-2) kidney tubular cells were approximately 1930- to 4760-fold higher than extracellular concentrations. Our study is the first to quantitatively measure the significant uptake of polymyxin in renal tubular cells and provides crucial information for the understanding of polymyxin-induced nephrotoxicity. Importantly, our approach represents a significant methodological advancement in determination of drug uptake for single-cell pharmacology.
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    Elevated labile Cu is associated with oxidative pathology in Alzheimer disease
    James, SA ; Volitakis, I ; Adlard, PA ; Duce, JA ; Masters, CL ; Cherny, RA ; Bush, AI (ELSEVIER SCIENCE INC, 2012-01-15)
    Oxidative stress is implicated in Alzheimer disease (AD) pathogenesis, for which evidence indicates that radical species are generated by the redox-active biometal Cu. The contribution of labile Cu to the oxidative stress observed in AD has not been evaluated. The Cu content of postmortem cortical tissue from nondemented elderly controls and AD cases was measured using inductively coupled plasma mass spectroscopy, and the proportion of labile Cu was assessed using the Cu-phenanthroline assay. Further, the capacity of the tissue to stabilize Cu(2+) was evaluated using immobilized metal-affinity chromatography, and the level of tissue oxidative damage was determined by the presence of thiobarbituric acid-reactive compounds. We identified elevated levels of exchangeable Cu(2+), which were correlated with tissue oxidative damage; additionally, we noted an increased capacity of AD cortical tissue samples to bind Cu(2+). This deranged Cu homeostasis reflects the homeostatic breakdown of Cu observed in AD and supports biometal metabolism as a therapeutic target.