Pharmacology, Toxicology and Environmental Health Commons^™

Effects Of Long-Term Pioglitazone Treatment On Peripheral And Central Markers Of Aging, Eric M. Blalock, Jeremiah T. Phelps, Tristano Pancani, James L. Searcy, Katie L. Anderson, John C. Gant, Jelena Popovic, Margarita G. Avdiushko, Don A. Cohen, Kuey-Chu Chen, Nada M. Porter, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARgamma) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer's disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Abeta accumulation. While TZD's actions in AD models help to elucidate the mechanisms underlying their potentially beneficial effects in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and …

Polychlorinated Biphenyl-Induced Endothelial Cell Dysfunction And Its Modulation By Dietary Lipids, Zuzana Majkova

University of Kentucky Doctoral Dissertations

Cardiovascular diseases are the number one cause of death in Western societies. Endothelial dysfunction is an early event in the pathology of atherosclerosis, which is an underlying cause in the majority of cardiovascular events. Exposure to persistent environmental pollutants, such as polychlorinated biphenyls (PCBs), is a risk factor for the development of atherosclerosis.

First, we tested a hypothesis that coplanar PCBs, dioxin-like chemicals with affinity for aryl hydrocarbon receptor (AhR), can stimulate up-regulation of monocyte chemoattractant protein-1 (MCP-1), an endothelium-derived chemokine that attracts monocytes into sub-endothelial space in early stages of atherosclerosis. Coplanar PCBs 77 and 126 increased expression of …

The Future (Or Lack Of Future) Of Personalized Prescription In Psychiatry, Jose De Leon

Psychiatry Faculty Publications

Rapid technological advances in genetics have created conceptual chaos regarding the genetics of drug response. Terms for differing concepts are used interchangeably: pharmacogenetics with pharmacogenomics, personalized medicine with personalized prescription. Biomarker has many definitions. The author prefers the concept of personalized prescription and uses it with implications beyond pharmacogenetics by considering all scientific information valid for prescribing medication. Genetics may not be crucial for all drugs. In this comprehensive view, clinicians must consider genetic, environmental and personal variables when prescribing medication and incorporate some basic pharmacological principles: (1) safety and efficacy, (2) pharmacokinetics and pharmacodynamics, (3) therapeutic window and prescriber's …

Insights Into Expression, Cellular Localization, And Regulation Of Supernatant Protein Factor, A Putative Regulator Of Cholesterol Biosynthesis, Elzbieta Ilona Stolarczyk

University of Kentucky Doctoral Dissertations

SPF (Supernatant Protein Factor) is a cytosolic protein that stimulates at least two enzymes in the cholesterol biosynthetic pathway: squalene monooxygenase and HMGCoA reductase. The mechanism of action has not been established but may be related to lipid transfer between intracellular membranes.

There are three human genes for SPF: SEC14L2 (SPF1), SEC14L3 (SPF2) and SEC14L4 (SPF3). The present study differentiates these closely related genes by evaluating their tissue-specific and relative expression levels. SPF1 mRNA was found to be most abundant in liver, mammary gland and stomach. SPF2 showed negligible expression in all tissues tested; SPF3 expression pattern was similar to …

Lipid Signaling In Brain Aging And Alzheimer's Disease: Pharmacologically Targeting Cholesterol Synthesis, Transport And Metabolism, James Lucas Searcy

University of Kentucky Doctoral Dissertations

The role cholesterol plays in the brain has long been underappreciated even though the brain contains a disproportionately high percentage of body cholesterol. Recent studies have found a link between the dysregulation of lipid metabolism and the risk of acquiring Alzheimer’s disease (AD) as well as a predisposition to cognitive decline. The goal of these studies was to elucidate the possible role lipid metabolism plays in pathological and normal brain aging by pharmacologically manipulating lipid metabolism and determining effects on key hippocampal biomarkers of AD and age-related cognitive decline. One series of experiments used an agonist (TO901317) to the liver …

Down-Regulation Of Ppargamma1 Suppresses Cell Growth And Induces Apoptosis In Mcf-7 Breast Cancer Cells, Yekaterina Y. Zaytseva, Xin Wang, R. Chase Southard, Natalie K. Wallis, Michael W. Kilgore

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily and is highly expressed in many human tumors including breast cancer. PPARgamma has been identified as a potential target for breast cancer therapy based on the fact that its activation by synthetic ligands affects the differentiation, proliferation, and apoptosis of cancer cells. However, the controversial nature of current studies and disappointing results from clinical trials raise questions about the contribution of PPARgamma signaling in breast cancer development in the absence of stimulation by exogenous ligands. Recent reports from both in vitro and in vivo studies …

Borderline Personality Disorder: An Overview Of History, Diagnosis And Treatment In Adolescents, Linah Al-Alem, Hatim A. Omar

Pharmacology and Nutritional Sciences Faculty Publications

Borderline personality disorder (BPD) is a cluster B personality disorder. It is characterized by erratic behaviors, emotional instability and one of its hallmarks is self injurious behavior, which starts in adolescence. Patients with BPD are difficult to treat, most have a history of child sexual abuse, about a quarter present with sexual abuse from a caretaker. Although personality disorders are diagnosed only in adults, BPD manifests itself in adolescence in the form of uncontrollable anger, self mutilations, dissociation and other such behaviors. Hence, there is a growing number of scientists discussing the possibility of diagnosing BPD in adolescents. Here, we …

Pgrmc1: A New Biomarker For The Estrogen Receptor In Breast Cancer, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

Estrogen receptor (ER) status is a critical biomarker in breast cancer, in large part because the ER is the target of tamoxifen and similar drugs. In the previous issue of Breast Cancer Research, Neubauer and colleagues used a proteomic approach to identify proteins that are differentially regulated by ER in breast tumors. The authors showed that ER-negative tumors have elevated levels of PGRMC1 (progesterone receptor membrane component-1), a hormone receptor component and binding partner for P450 proteins. In contrast, PGRMC1 was phosphorylated in ER-positive tumors. The staining patterns of ER and PGRMC1 were mutually exclusive in breast tumor sections, and …

The Influence Of Citrate, Maltolate And Fluoride On The Gastrointestinal Absorption Of Aluminum At A Drinking Water-Relevant Concentration: A 26Al And 14C Study, Yuzhao Zhou, Wesley R. Harris, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

The objectives were to test the null hypotheses that (1) citrate, maltolate, and fluoride do not significantly influence oral Al bioavailability, C_max or T_max at an Al dose relevant to drinking water exposure; and (2) Al citrate and maltolate are absorbed intact from the gastrointestinal tract. Male Fisher rats were given 1 ml of solution intra-gastrically containing 1 nCi ²⁶Al (65 nmol total Al) as the Al³⁺ ion, or as complexes with ¹⁴C-citrate, ¹⁴C-maltolate or fluoride, during concurrent ²⁷Al iv infusion. Blood was repeatedly collected for serum ²⁶Al, total Al and ^{14 …}

The Α1d-Adrenergic Receptor Is Expressed Intracellularly And Coupled To Increases In Intracellular Calcium And Reactive Oxygen Species In Human Aortic Smooth Muscle Cells, Mary L. García-Cazarín, Jennifer L. Smith, Kyle A. Olszewski, Dan F. Mccune, Linda A. Simmerman, Robert W. Hadley, Susan D. Kraner, Michael T. Piascik

Pharmacology and Nutritional Sciences Faculty Publications

Background: The cellular localization of the α_1D-adrenergic receptor (α_1D-AR) is controversial. Studies in heterologous cell systems have shown that this receptor is expressed in intracellular compartments. Other studies show that dimerization with other ARs promotes the cell surface expression of the α_1D-AR. To assess the cellular localization in vascular smooth muscle cells, we developed an adenoviral vector for the efficient expression of a GFP labeled α_1D-AR. We also measured cellular localization with immunocytochemistry. Intracellular calcium levels, measurement of reactive oxygen species and contraction of the rat aorta were used as measures of …

The Metastasis Suppressor Nm23-H1 Is Required For Dna Repair, Mengmeng Yang

University of Kentucky Doctoral Dissertations

NM23-H1 represents the first identified metastasis suppressor, exhibiting reduced expression in breast carcinoma and melanoma, and an ability to inhibit metastatic growth without significant impact on the transformed phenotype. Although its molecular mechanism of action is not fully understood, NM23-H1 possesses at least three enzymatic activities that may mediate metastasis suppressor function. It catalyzes nucleoside diphosphate kinase (NDPK) activity, as well as protein histidine kinase and 3’-5’ exonuclease activities. As 3’-5’ exonucleases are generally required for maintenance of genomic integrity, this activity represents a plausible mediator to underlie the metastasis suppressor function of NM23-H1 protein. To investigate the relevant activity …

Post Hoc Pattern Matching: Assigning Significance To Statistically Defined Expression Patterns In Single Channel Microarray Data, Randall Hulshizer, Eric M. Blalock

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Researchers using RNA expression microarrays in experimental designs with more than two treatment groups often identify statistically significant genes with ANOVA approaches. However, the ANOVA test does not discriminate which of the multiple treatment groups differ from one another. Thus, post hoc tests, such as linear contrasts, template correlations, and pairwise comparisons are used. Linear contrasts and template correlations work extremely well, especially when the researcher has a priori information pointing to a particular pattern/template among the different treatment groups. Further, all pairwise comparisons can be used to identify particular, treatment group-dependent patterns of gene expression. However, these approaches …

Expansion Of The Calcium Hypothesis Of Brain Aging And Alzheimer's Disease: Minding The Store, Olivier Thibault, John C. Gant, Philip W. Landfield

Pharmacology and Nutritional Sciences Faculty Publications

Evidence accumulated over more than two decades has implicated Ca2+ dysregulation in brain aging and Alzheimer's disease (AD), giving rise to the Ca2+ hypothesis of brain aging and dementia. Electrophysiological, imaging, and behavioral studies in hippocampal or cortical neurons of rodents and rabbits have revealed aging-related increases in the slow afterhyperpolarization, Ca2+ spikes and currents, Ca2+transients, and L-type voltage-gated Ca2+ channel (L-VGCC) activity. Several of these changes have been associated with age-related deficits in learning or memory. Consequently, one version of the Ca2+ hypothesis has been that increased L-VGCC activity drives many of the other Ca2+-related biomarkers of hippocampal aging. …

Xenobiotic Transporters In Lactating Mammary Epithelial Cells: Predictions For Drug Accumulation In Breast Milk, Philip Earle Empey

Theses and Dissertations--Pharmacy

Recent literature has established that breast cancer resistance protein (ABCG2) is upregulated during lactation and is responsible for the greater than predicted accumulation of many drugs in breast milk. The objectives of this project were (1) to investigate the role of this transporter in the reported apically-directed nitrofurantoin flux in the CIT3 cell culture model of lactation, (2) to develop a mathematical model for drug transfer into breast milk to relate initial flux rates, steady-state concentrations, efflux ratios, and in vivo milk to serum ratios (M/S) and (3) to identify xenobiotic transporters that are highly expressed, and therefore potentially important …

The Speciation Of Metals In Mammals Influences Their Toxicokinetics And Toxicodynamics And Therefore Human Health Risk Assessment, Robert A. Yokel, Stephen M. Lasley, David C. Dorman

Pharmaceutical Sciences Faculty Publications

Chemical form (i.e., species) can influence metal toxicokinetics and toxicodynamics and should be considered to improve human health risk assessment. Factors that influence metal speciation (and examples) include: (1) carrier-mediated processes for specific metal species (arsenic, chromium, lead and manganese), (2) valence state (arsenic, chromium, manganese and mercury), (3) particle size (lead and manganese), (4) the nature of metal binding ligands (aluminum, arsenic, chromium, lead, and manganese), (5) whether the metal is an organic versus inorganic species (arsenic, lead, and mercury), and (6) biotransformation of metal species (aluminum, arsenic, chromium, lead, manganese and mercury). The influence of speciation on metal …

Manganese Distribution Across The Blood-Brain Barrier. Iv. Evidence For Brain Influx Through Store-Operated Calcium Channels, Janelle S. Crossgrove, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is a required co-factor for many ubiquitous enzymes; however, chronic Mn overexposure can cause manganism, a parkinsonian-like syndrome. Previous studies showed Mn influx into brain is carrier-mediated, though the putative carrier(s) were not established. Studies conducted with cultured bovine brain microvascular endothelial cells (bBMECs), which comprise the blood–brain barrier, revealed ⁵⁴Mn (II) uptake positively correlated with pH, was temperature-dependent, and was sodium- and energy-independent. Brain ⁵⁴Mn uptake correlated inversely with calcium (Ca) concentration, but ⁴⁵Ca uptake was unaltered by high Mn concentration. Lanthanum (La), a non-selective inhibitor of several Ca channel types, as well as …

Manganese Distribution Across The Blood-Brain Barrier. I. Evidence For Carrier-Mediated Influx Of Managanese Citrate As Well As Manganese And Manganese Transferrin, Janelle S. Crossgrove, David D. Allen, Bonny L. Bukaveckas, Susan S. Rhineheimer, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is an essential element and a neurotoxicant. Regulation of Mn movement across the blood–brain barrier (BBB) contributes to whether the brain Mn concentration is functional or toxic. In plasma, Mn associates with water, small molecular weight ligands and proteins. Mn speciation may influence the kinetics of its movement through the BBB. In the present work, the brain influx rates of ⁵⁴Mn²⁺, ⁵⁴Mn citrate and ⁵⁴Mn transferrin (⁵⁴Mn Tf) were determined using the in situ brain perfusion technique. The influx rates were compared to their predicted diffusion rates, which were determined from …

The Toxicology Of Aluminum In The Brain: A Review, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Aluminum is environmentally ubiquitous, providing human exposure. Usual human exposure is primarily dietary. The potential for significant Al absorption from the nasal cavity and direct distribution into the brain should be further investigated. Decreased renal function increases human risk of Al-induced accumulation and toxicity. Brain Al entry from blood may involve transferrin-receptor mediated endocytosis and a more rapid process transporting small molecular weight Al species. There appears to be Al efflux from the brain, probably as Al citrate. There is prolonged retention of a fraction of Al that enters the brain, suggesting the potential for accumulation with repeated exposure. Al …

Toxicological Studies On Aquatic Contaminants Originating From Coal Production And Utilization: The Induction Of Tolerance To Silver In Laboratory Populations Of Fish And The Chronic Toxicity Of Nickel To Fish Early Life Stages, Wesley J. Birge, Jeffrey A. Black, James F. Hobson, Albert G. Westerman

KWRRI Research Reports

Aquatic toxicity studies were performed on two important coal-derived contaminants, silver and nickel. Silver was investigated with regard to metal-induced tolerance in laboratory populations of the fathead minnow (Pimephales promelas). Fish were exposed to acute silver concentrations following acclimation to sublethal exposures of this metal. Based on median lethal times (LT50), animals which had received 14 days prior exposure to 1.5 and 15 μg Ag/L were three to four times more resistant to silver than were previously unexposed organisms. This metal-induced resistance was not a sustained response. After organisms which had been acclimated to 15 μg/L had been transferred to …

The Induction Of Tolerance To Heavy Metals In Natural And Laboratory Populations Of Fish, Wesley J. Birge, William H. Benson, Jeffrey A. Black

KWRRI Research Reports

Aquatic toxicity studies were performed on two natural populations of fathead minnows. One group of organisms was taken from a metal-contaminated flyash pond associated with a coal-fired power plant and the other group was collected from relatively uncontaminated hatchery ponds. Acute tests indicated that flyash pond fish were significantly more tolerant to cadmium and copper than were hatchery fish. At an exposure concentration of 6.0 mg Cd/L in moderately hard water, the median period of survival for flyash pond fish was 50.0 hr compared to 6.8 hr for hatchery fish. Both groups of organisms were about equally sensitive to zinc. …

Effects Of Organic Compounds On Amphibian Reproduction, Wesley J. Birge, Jeffrey A. Black, Robert A. Kuehne

KWRRI Research Reports

Aquatic toxicity tests were conducted with atrazine, carbon tetrachloride, chloroform, methylene chloride, trisodium nitrilotriacetic acid (NTA), and phenol. Each compound was administered to developmental stages of three to five amphibian species. Exposure was initiated at fertilization and maintained through 4 days posthatching. Test responses included lethality and teratogenesis. Different amphibian species exhibited varying degrees of tolerance to the selected compounds. Greatest tolerance usually was observed for the more broadly adapted semi-aquatic and terrestrial species (e.g., Bufo americanus, Bufo fowleri). The more sensitive amphibians usually included those species which normally are restricted to aquatic or moist habitats (e.g., Rana …