Medicine and Health Sciences Commons^™

Cyclooxygenase-2 Inhibition Attenuates Abdominal Aortic Aneurysm Progression In Hyperlipidemic Mice, Sarbani Ghoshal, Charles D Loftin

Pharmaceutical Sciences Faculty Publications

Abdominal aortic aneurysms (AAAs) are a chronic inflammatory disease that increase the risk of life-threatening aortic rupture. In humans, AAAs have been characterized by increased expression of cyclooxygenase-2 and the inactivation of COX-2 prior to disease initiation reduces AAA incidence in a mouse model of the disease. The current study examined the effectiveness of selective cyclooxygenase-2 (COX-2) inhibition on reducing AAA progression when administered after the initiation of AAA formation. AAAs were induced in hyperlipidemic apolipoprotein E-deficient mice by chronic angiotensin II (AngII) infusion and the effect of treatment with the COX-2 inhibitor celecoxib was examined when initiated at different …

Brain Microvascular Endothelial Cell Association And Distribution Of A 5 Nm Ceria Engineered Nanomaterial, Mo Dan, Michael T. Tseng, Peng Wu, Jason M. Unrine, Eric A. Grulke, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

PURPOSE: Ceria engineered nanomaterials (ENMs) have current commercial applications and both neuroprotective and toxic effects. Our hypothesis is that ceria ENMs can associate with brain capillary cells and/or cross the blood-brain barrier.

METHODS: An aqueous dispersion of ∼5 nm ceria ENM was synthesized and characterized in house. Its uptake space in the Sprague Dawley rat brain was determined using the in situ brain perfusion technique at 15 and 20 mL/minute flow rates; 30, 100, and 500 μg/mL ceria perfused for 120 seconds at 20 mL/minute; and 30 μg/mL perfused for 20, 60, and 120 seconds at 20 mL/minute. The capillary …

Modeling Of Pharmacokinetics Of Cocaine In Human Reveals The Feasibility For Development Of Enzyme Therapies For Drugs Of Abuse, Fang Zheng, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly …

Localization And Functional Characterization Of The Rat Oatp4c1 Transporter In An In Vitro Cell System And Rat Tissues, Kuei-Ling Kuo, Haining Zhu, Patrick J. Mcnamara, Markos Leggas

Pharmaceutical Sciences Faculty Publications

The organic anion transporting polypeptide 4c1 (Oatp4c1) was previously identified as a novel uptake transporter predominantly expressed at the basolateral membrane in the rat kidney proximal tubules. Its functional role was suggested to be a vectorial transport partner of an apically-expressed efflux transporter for the efficient translocation of physiological substrates into urine, some of which were suggested to be uremic toxins. However, our in vitro studies with MDCKII cells showed that upon transfection rat Oatp4c1 polarizes to the apical membrane. In this report, we validated the trafficking and function of Oatp4c1 in polarized cell systems as well as its subcellular …

A Humanized Pattern Of Aromatase Expression Is Associated With Mammary Hyperplasia In Mice, Hong Zhao, Elizabeth K. Pearson, David C. Brooks, John S. Coon, Dong Chen, Masashi Demura, Ming Zhang, Charles V. Clevenger, Xia Xu, Timothy D. Veenstra, Robert T. Chatterton, Francesco J. Demayo, Serdar E. Bulun

Pharmaceutical Sciences Faculty Publications

Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Arom(hum) mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast …

Hormone-Induced 14-3-3Γ Adaptor Protein Regulates Steroidogenic Acute Regulatory Protein Activity And Steroid Biosynthesis In Ma-10 Leydig Cells, Yasaman Aghazadeh, Malena B. Rone, Josip Blonder, Xiaoying Ye, Timothy D. Veenstra, D. Buck Hales, Martine Culty, Vassilios Papadopoulos

Pharmaceutical Sciences Faculty Publications

Cholesterol is the sole precursor of steroid hormones in the body. The import of cholesterol to the inner mitochondrial membrane, the rate-limiting step in steroid biosynthesis, relies on the formation of a protein complex that assembles at the outer mitochondrial membrane called the transduceosome. The transduceosome contains several mitochondrial and cytosolic components, including the steroidogenic acute regulatory protein (STAR). Human chorionic gonadotropin (hCG) induces de novo synthesis of STAR, a process shown to parallel maximal steroid production. In the hCG-dependent steroidogenic MA-10 mouse Leydig cell line, the 14-3-3γ protein was identified in native mitochondrial complexes by mass spectrometry and immunoblotting, …

Distribution, Elimination, And Biopersistence To 90 Days Of A Systemically Introduced 30 Nm Ceria-Engineered Nanomaterial In Rats, Robert A. Yokel, Tu C. Au, Robert Macphail, Sarita S. Hardas, D. Allan Butterfield, Rukhsana Sultana, Michael Goodman, Michael T. Tseng, Mo Dan, Hamed Haghnazar, Jason M. Unrine, Uschi M. Graham, Peng Wu, Eric A. Grulke

Pharmaceutical Sciences Faculty Publications

Nanoceria is used as a catalyst in diesel fuel, as an abrasive in printed circuit manufacture, and is being pursued as an antioxidant therapeutic. Our objective is to extend previous findings showing that there were no reductions of cerium in organs of the mononuclear phagocyte (reticuloendothelial) system up to 30 days after a single nanoscale ceria administration. An ~5% aqueous dispersion of citrate-stabilized 30 nm ceria, synthesized and characterized in-house, or vehicle, was iv infused into rats terminated 1, 7, 30, or 90 days later. Cageside observations were obtained daily, body weight weekly. Daily urinary and fecal cerium outputs were …

Concentration Of Endogenous Estrogens And Estrogen Metabolites In The Nci-60 Human Tumor Cell Lines, Xia Xu, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Endogenous estrogens and estrogen metabolites play an important role in the pathogenesis and development of human breast, endometrial, and ovarian cancers. Increasing evidence also supports their involvement in the development of certain lung, colon and prostate cancers.

METHODS: In this study we systemically surveyed endogenous estrogen and estrogen metabolite levels in each of the NCI-60 human tumor cell lines, which include human breast, central nerve system, colon, ovarian, prostate, kidney and non-small cell lung cancers, as well as melanomas and leukemia. The absolute abundances of these metabolites were measured using a liquid chromatography-tandem mass spectrometry method that has been …

Metabolomics: The Final Frontier?, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

No abstract provided.

Pressure-Assisted Protein Extraction: A Novel Method For Recovering Proteins From Archival Tissue For Proteomic Analysis, Carol B. Fowler, Timothy J. Waybright, Timothy D. Veenstra, Timothy J. O'Leary, Jeffrey T. Mason

Pharmaceutical Sciences Faculty Publications

Formaldehyde-fixed, paraffin-embedded (FFPE) tissue repositories represent a valuable resource for the retrospective study of disease progression and response to therapy. However, the proteomic analysis of FFPE tissues has been hampered by formaldehyde-induced protein modifications, which reduce protein extraction efficiency and may lead to protein misidentification. Here, we demonstrate the use of heat augmented with high hydrostatic pressure (40,000 psi) as a novel method for the recovery of intact proteins from FFPE mouse liver. When FFPE mouse liver was extracted using heat and elevated pressure, there was a 4-fold increase in protein extraction efficiency, a 3-fold increase in the extraction of …

Comparison Of Estrone And 17Β-Estradiol Levels In Commercial Goat And Cow Milk, D. W. Farlow, X. Xu, T. D. Veenstra

Pharmaceutical Sciences Faculty Publications

Increased levels of estrogen metabolites are believed to be associated with cancers of the reproductive system. One potential dietary source of these metabolites that is commonly consumed worldwide is milk. In North America, dairy cows are the most common source of milk; however, goats are the primary source of milk worldwide. In this study, the absolute concentrations of unconjugated and total (unconjugated plus conjugated) estrone (E(1)) and 17β-estradiol (E(2)) were compared in a variety of commercial cow milks (regular and organic) and goat milk. A lower combined concentration of E(1) and E(2) was found in goat milk than in any …

Phosphatidylserine Colocalizes With Epichromatin In Interphase Nuclei And Mitotic Chromosomes, Igor Prudovsky, Calvin P.H. Vary, Yolanda Markaki, Ada L. Olins, Donald E. Olins

Pharmaceutical Sciences Faculty Publications

Cycling eukaryotic cells rapidly re-establish the nuclear envelope and internal architecture following mitosis. Studies with a specific anti-nucleosome antibody recently demonstrated that the surface (“epichromatin”) of interphase and mitotic chromatin possesses a unique and conserved conformation, suggesting a role in postmitotic nuclear reformation. Here we present evidence showing that the anionic glycerophospholipid phosphatidylserine is specifically located in epichromatin throughout the cell cycle and is associated with nucleosome core histones. This suggests that chromatin bound phosphatidylserine may function as a nucleation site for the binding of ER and re-establishment of the nuclear envelope.

Aluminum In Food – The Nature And Contribution Of Food Additives, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

No abstract provided.

Looking Back At Genomic Medicine In 2011, Charles Auffray, Timothy Caulfield, Muin J. Khoury, James R. Lupski, Matthias Schwab, Timothy Veenstra

Pharmaceutical Sciences Faculty Publications

No abstract provided.

Combination Effects Of Docetaxel And Doxorubicin In Hormone-Refractory Prostate Cancer Cells, Eleftheria Tsakalozou, Allison M. Eckman, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Combination effects of docetaxel (DOC) and doxorubicin (DOX) were investigated in prostate cancer cells (PC3 and DU145). Combination indices (CIs) were determined using the unified theory in various concentrations and mixing ratios (synergy: CI < 0.9, additivity: 0.9 < CI < 1.1, and antagonism: CI > 1.1). DOC showed a biphasic cytotoxicity pattern with the half maximal inhibitory concentration (IC50) at the picomolar range for PC3 (0.598 nM) and DU145 (0.469 nM), following 72 h drug exposure. The IC50s of DOX were 908 nM and 343 nM for PC3 and DU145, respectively. Strong synergy was seen when PC3 was treated with DOC at concentrations lower than its IC50 values (0.125~0.5 nM) plus …

The Pharmacokinetics And Toxicology Of Aluminum In The Brain, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

The chemical forms (species) of aluminum in blood plasma and brain extracellular fluid are considered, as they are the candidates for brain aluminum uptake and efflux. The blood-brain barrier is the primary site of brain aluminum uptake. The mechanism of brain uptake of aluminum transferrin, long thought to be mediated by transferrin-receptor mediated endocytosis, requires further investigation. Brain Al citrate uptake has been attributed to the sodium-independent Lglutamate/ L-cystine exchanger system, system Xc-. Reports have suggested aluminum can compromise blood-brain barrier integrity, however the studies were conducted with aluminum concentrations greatly exceeding those seen in human blood plasma. Aluminum appeared …

Ceria-Engineered Nanomaterial Distribution In, And Clearance From, Blood: Size Matters, Mo Dan, Peng Wu, Eric A. Grulke, Uschi M. Graham, Jason M. Unrine, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

AIMS: Characterize different sized ceria-engineered nanomaterial (ENM) distribution in, and clearance from, blood (compared to the cerium ion) following intravenous infusion.

MATERIALS & METHODS: Cerium (Ce) was quantified in whole blood, serum and clot (the formed elements) up to 720 h.

RESULTS: Traditional pharmacokinetic modeling showed best fit for 5 nm ceria ENM and the cerium ion. Ceria ENMs larger than 5 nm were rapidly cleared from blood. After initially declining, whole blood 15 and 30 nm ceria increased (results that have not been well-described by traditional pharmacokinetic modeling). The cerium ion and 5 and 55 nm ceria did not …

Histone Demethylase Jumonji D3 (Jmjd3) As A Tumor Suppressor By Regulating P53 Protein Nuclear Stabilization., Chibawanye I. Ene, Lincoln Edwards, Gregory Riddick, Mehmet Baysan, Kevin Woolard, Svetlana Kotliarova, Chen Lai, Galina Belova, Maggie Cam, Jennifer Walling, Ming Zhou, Holly Stevenson, Hong Sug Kim, Keith Killian, Timothy Veenstra, Rolanda Bailey, Hua Song, Wei Zhang, Howard A. Fine

Pharmaceutical Sciences Faculty Publications

Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate …