Stevenson University Beverly K. Fine School of the Sciences Faculty and Staff Works

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    You're doing it wrong Think you know how to recycle? As Earth Day approaches, think again
    (The Baltimore Sun, 2017-04-21) Tucker, Kimberly Pause; Environmental Science
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    Utilizing Ayurvedic literature for the identification of novel phytochemical inhibitors of botulinum neurotoxin A
    (Journal of Ethnopharmacology, 2017-02-02) Yalamanchili, Chinni; Manda, Vamshi K.; Chittiboyina, Amar G.; Guernieri, Rebecca L.; Harrell, William A. Jr.; Webb, Robert P.; Smith, Leonard A.; Khan, Ikhlas A.; Chemistry
    Ethnopharmacological relevance Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to identify novel phytochemicals for the inhibition of bacterial exotoxin, botulinum neurotoxin A (BoNT/A) based on Ayurvedic literature. BoNT/A is released by Clostridium species, which when ingested, inhibits the release of acetylcholine by concentrating at the neuromuscular junction and causes flaccid paralysis, resulting in a condition termed as botulism, and may also lead to death due to respiratory arrest. Results From the docking scores and structural diversity, nine compounds including acoric acid 1, three flavonoids, three coumarins derivatives, one kava lactone were selected and screened using an in vitro HPLC-based protease assay. The bioassay results showed that several compounds possess BoNT/A LC inhibition of 50–60% when compared to positive controls NSC 84094 and CB7967495 (80–95%). Conclusion Further testing of the active compounds identified from Ayurvedic literature and structure-activity studies of acoric acid 1 using more sensitive bioassays is under way. The identification of acoric acid 1, a novel scaffold against BoNT/A, exemplifies the utility of Ayurvedic literature for the discovery of novel drug leads.
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    A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A
    (Bioorganic & Medicinal Chemistry Letters, 2017-02-01) Harrell, William A. Jr.; Vieira, Rebecca C.; Ensel, Susan M.; Montgomery, Vicki; Guernieri, Rebecca; Eccard, Vanessa S.; Campbell, Yvette; Roxas-Duncan, Virginia; Cardellina, John H. II; Webb, Robert P.; Smith, Leonard A.; Chemistry
    Our initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC50 values ⩽1μM and 11 effective at ⩽2μM in an ex vivo assay.
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    Measurement of Oxygen Concentrations in the Intact Beating Heart Using Electron Paramagnetic Resonance Spectroscopy: A Technique for Measuring Oxygen Concentrations in Situ
    (Journal of Bioenergetics and Biomembranes, 1991-12) Zweier, Jay L.; Thompson-Gorman, Susan; Kuppusamy, Periannan; Beverly K. Fine School of the Sciences
    Electron paramagnetic resonance (EPR) spectroscopy can be applied to measure oxygen concentrations in cells and tissues. Oxygen is paramagnetic, and thus it interacts with a free radical label resulting in a broadening of the observed linewidth. Recently we have developed instrumentation in order to enable the performance of EPR spectroscopy and EPR oximetry in the intact beating heart. This spectrometer consists of 1–2-GHz microwave bridge with the source locked to the resonant frequency of a specially designed lumped circuit resonator. This technique is applied to measure the kinetics of the uptake and clearance of different free radical labels. It is demonstrated that this technique can be used to noninvasively measure tissue oxygen concentration. In addition, rapid scan EPR measurements can be performed enabling gated millisecond measurements of oxygen concentrations to be performed over the cardiac cycle. Thus, low-frequency EPR spectroscopy offers great promise in the study of tissue oxygen concentrations and the role of oxygen in metabolic control.
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    Determination of the Mechanism of Free Radical in Human Aortic Endothelial Cells Exposed to Anoxia and Reoxygenation
    (The Journal of Biological Chemistry, 1994-09-30) Zweier, Jay L.; Broderick, Raymond; Kuppusamy, Periannan; Thompson-Gorman, Susan; Lutty, Gerard A.; Beverly K. Fine School of the Sciences
    Endothelial cell-derived oxygen free radicals are important mediators of postischemic injury; however, the mechanisms that trigger this radical generation are not known, and it is not known if this process can occur in human cells and tissues. The enzyme xanthine oxidase can be an important source of radical generation; however, it has been reported that this enzyme may not be present in human endothelium. To determine the presence and mechanisms of radical generation in human vascular endothelial cells subjected to anoxia and reoxygenation, electron paramagnetic resonance measurements were performed on cultured human aortic endothelial cells using the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). These measurements were correlated with cellular injury, xanthine oxidase activity, and alterations in cellular nucleotides. Upon reoxygenation after 60 min of anoxia, large DMPO-OH (aN = aH = 14.9 G) and smaller DMPO-R (aN = 15.8 G, aH = 22.8 G) signals were seen. Superoxide dismutase totally quenched this radical generation. The ferric iron chelator deferoxamine prevented cell death and totally quenched the DMPO-R signal with a 40% decrease in the DMPO-OH signal. Xanthine oxidase was shown to be present in these cells and to be the primary source of free radicals. While the concentration of this enzyme did not change after anoxia, the concentration of its substrate, hypoxanthine, markedly increased, resulting in increased free radical generation upon reoxygenation. Thus, reoxygenated human vascular endothelial cells generate superoxide free radicals, which further react with iron to form the reactive hydroxyl radical, which in turn causes cell death. Xanthine oxidase was the primary source of radical generation with this process triggered by the breakdown of ATP to the substrate hypoxanthine during anoxia.