Scholarly Works, Virginia-Maryland College of Veterinary Medicine
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Browsing Scholarly Works, Virginia-Maryland College of Veterinary Medicine by Department "Human Nutrition, Foods, and Exercise"
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- Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung FunctionMcDaniel, Dylan K.; Ringel-Scaia, Veronica M.; Morrison, Holly A.; Coutermarsh-Ott, Sheryl; Council-Troche, McAlister; Angle, Jonathan W.; Perry, Justin B.; Davis, Grace; Leng, Weinan; Minarchick, Valerie; Yang, Yi; Chen, Bo; Reece, Sky W.; Brown, David A.; Cecere, Thomas E.; Brown, Jared M.; Gowdy, Kymberly M.; Hochella, Michael F. Jr.; Allen, Irving C. (Frontiers, 2019-11-28)Coal is one of the most abundant and economic sources for global energy production. However, the burning of coal is widely recognized as a significant contributor to atmospheric particulate matter linked to deleterious respiratory impacts. Recently, we have discovered that burning coal generates large quantities of otherwise rare Magnéli phase titanium suboxides from TiO2 minerals naturally present in coal. These nanoscale Magnéli phases are biologically active without photostimulation and toxic to airway epithelial cells in vitro and to zebrafish in vivo. Here, we sought to determine the clinical and physiological impact of pulmonary exposure to Magnéli phases using mice as mammalian model organisms. Mice were exposed to the most frequently found Magnéli phases, Ti6O11, at 100 parts per million (ppm) via intratracheal administration. Local and systemic titanium concentrations, lung pathology, and changes in airway mechanics were assessed. Additional mechanistic studies were conducted with primary bone marrow derived macrophages. Our results indicate that macrophages are the cell type most impacted by exposure to these nanoscale particles. Following phagocytosis, macrophages fail to properly eliminate Magnéli phases, resulting in increased oxidative stress, mitochondrial dysfunction, and ultimately apoptosis. In the lungs, these nanoparticles become concentrated in macrophages, resulting in a feedback loop of reactive oxygen species production, cell death, and the initiation of gene expression profiles consistent with lung injury within 6 weeks of exposure. Chronic exposure and accumulation of Magnéli phases ultimately results in significantly reduced lung function impacting airway resistance, compliance, and elastance. Together, these studies demonstrate that Magnéli phases are toxic in the mammalian airway and are likely a significant nanoscale environmental pollutant, especially in geographic regions where coal combustion is a major contributor to atmospheric particulate matter.
- Regulation of Cytoskeleton Organization by Sphingosine in a Mouse Cell Model of Progressive Ovarian CancerCreekmore, Amy L.; Heffron, C. Lynn; Brayfield, Bradley P.; Roberts, Paul C.; Schmelz, Eva M. (MDPI, 2013-07-16)Ovarian cancer is a multigenic disease and molecular events driving ovarian cancer progression are not well established. We have previously reported the dysregulation of the cytoskeleton during ovarian cancer progression in a syngeneic mouse cell model for progressive ovarian cancer. In the present studies, we investigated if the cytoskeleton organization is a potential target for chemopreventive treatment with the bioactive sphingolipid metabolite sphingosine. Long-term treatment with non-toxic concentrations of sphingosine but not other sphingolipid metabolites led to a partial reversal of a cytoskeleton architecture commonly associated with aggressive cancer phenotypes towards an organization reminiscent of non-malignant cell phenotypes. This was evident by increased F-actin polymerization and organization, a reduced focal adhesion kinase expression, increased a-actinin and vinculin levels which together led to the assembly of more mature focal adhesions. Downstream focal adhesion signaling, the suppression of myosin light chain kinase expression and hypophosphorylation of its targets were observed after treatment with sphingosine. These results suggest that sphingosine modulate the assembly of actin stress fibers via regulation of focal adhesions and myosin light chain kinase. The impact of these events on suppression of ovarian cancer by exogenous sphingosine and their potential as molecular markers for treatment efficacy warrants further investigation.