Pharmacology, Toxicology and Environmental Health Commons^™

Kv7 K+ Channels In Airway Smooth Muscle Cells As Target For Asthma Therapy, Priyanka Prakash Kakad

Master's Theses

Airway hyperresponsiveness (AHR) is an important etiological feature of asthma, the molecular mechanisms of which are poorly understood, thus preventing development of specific and effective therapies. We investigate the role played by Kv7 voltage-activated potassium channels in the pathophysiology of AHR and evaluate the significance of their regulation in treatment of asthma. Our studies provide the first evidence for expression of multiple Kv7 channels in guinea pig and human airways and demonstrate that the expression of Kv7 channels is reduced in allergen-sensitized guinea pig airways. Our ex vivo functional studies reveal that clinically available Kv7 channel activators attenuate the bronchoconstrictor …

Mutation In The Plasmodium Falciparum Crt Protein Determines The Stereospecific Activity Of Antimalarial Cinchona Alkaloids, Carol E. Griffin, Jonathan M. Hoke, Upeka Samarakoon, Junhui Duan, Jianbing Mu, Michael T. Ferdig, David C. Warhurst, Roland A. Cooper

Biological Sciences Faculty Publications

The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (-)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (-)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in …

The Proton-Coupled Folate Transporter: Biology And Therapeutic Applications To Cancer, Sita Desmoulin

Wayne State University Dissertations

Folates are essential cofactors of tumor cell proliferation and survival required for nucleotide biosynthesis and amino acid metabolism. In cancer therapy, inhibition of folate-dependent metabolic pathways has been achieved through the use of antifolates. Unfortunately, the efficacy of many clinically approved antifolates is limited by a lack of tumor selectivity. Facilitative transport of folates into mammalian cells is achieved by the reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT). As PCFT is a folate-proton symporter with an acidic pH optimum, PCFT may provide a mechanism for targeting cytotoxic antifolates to tumors, based on their acidic microenvironments. To establish the …

Studies On Waterborne Cadmium Exposure To Lymnaea Stagnalis In Varying Water Qualities And The Development Of A Novel Tissue Residue Approach, Nish M. Pais

Theses and Dissertations (Comprehensive)

Recent studies have shown that the use of bioaccumulation (tissue residues) as a predictor for toxic effects for metals is a flawed concept.Adams et al. (2010) suggested a novel tissue residue approach (TRA) in which bioaccumulation in resistant organismsis related to toxic effects in sensitive organisms. The goal of this thesis was to test these assumptions in relation to Cd exposure using the great pond snail, Lymnaea stagnalis by developing and improving the understanding of Cd accumulationin aquatic invertebrates.

The relationship between Cd bioaccumulation and its toxicity was studied in L. stagnalisusing acute (96h) and chronic (one month) …

Maternal Immune Dysregulation In The Pathogenesis Of Neurodevelopmental Disorders: Interleukin-6 As A Central Mechanism And Therapeutic Target Of Flavonoids, Ellisa Carla Parker-Athill

USF Tampa Graduate Theses and Dissertations

Activation of the maternal immune system and resultant maternal cytokine expression due to prenatal infection has been implicated as a significant contributor to the pathology of neuropsychiatric and neurodevelopmental disorders such as schizophrenia and Autism Spectrum Disorder (ASD). Increased maternal interleukin-6 (IL-6) expression, observed clinically and in animal models of prenatal infection, and resultant activation of key signaling pathways, has been shown to be a biological indicator of pathology, and a central component of the pathological mechanism. In animal models of prenatal infection and clinically in pregnancy disorders hallmarked by immunological irregularities and increased IL-6 expression, inhibition of IL-6 has …

Modulating The Pharmacokinetics Of Bioflavonoids, Adam John Smith

USF Tampa Graduate Theses and Dissertations

One of the largest obstacles in drug development is to overcome solubility and bioavailability problems. Preformulation strategies such as nanoparticle formation are often employed but sometimes create new issues and are limited in their effectiveness and applications. Since the majority of drugs are marketed and sold as solid forms, drug delivery systems are not always desirable. This is where solid-state chemistry becomes important. Traditional solid-state chemistry approaches are often successful but are sometimes too restrictive and cannot be applied to certain compounds. Cocrystals have emerged as an alternative solid-state technique that can be applied to a broad range of compounds. …

Targeting Α4 Integrin Containing Complexes In Multiple Myeloma Using Peptidomimetics, Michael Foster Emmons

USF Tampa Graduate Theses and Dissertations

In our previous work we demonstrated that the integrin antagonist, HYD1, induced necrotic cell death in myeloma cell lines in vitro and in vivo as a single agent. In order to further delineate biomarkers of response to HYD1 we developed an isogenic drug resistant variant named H929-60. We show that the acquisition of resistance towards HYD1 correlates with reduced expression of the cleaved α4 integrin subunit and beta 1 integrin. Moreover, we demonstrate that HYD1 interacts with α4 integrin in myeloma cells. Consistent with reduced VLA-4 expression, the resistant variant showed ablated functional binding to fibronectin, VCAM-1 and the bone …

Use And Development Of Computational Tools In Drug Discovery: From Small Molecules To Cyclic Peptides, Daniel Navarrete Santiago

USF Tampa Graduate Theses and Dissertations

The scope of this work focuses on computationally modeling compounds with protein structures. While the impetus of drug discovery is the innovation of new therapeutic molecules, it also involves distinguishing molecules that would not be an effective drug. This can be achieved by inventing new tools or by refining old tools. Virtual screening (VS, also called docking), the computational modeling of a molecule in a receptor structure, is a staple in predicting a molecule's affinity for an intended target. In our Virtual Target Screening system (also called inverse-docking), VS is used to find high-affinity targets, which can potentially explain absorption, …

Effects Of 17Α-Ethinylestradiol (Ee2) On Reproductive Endocrine Status In Mummichog (Fundulus Heteroclitus) Under Differing Salinity And Temperature Conditions, Esteban Gillio Meina

Theses and Dissertations (Comprehensive)

Waterborne exposure to 17α-ethinylestradiol (EE₂), a synthetic estrogen, has previously been shown to decrease reproductive endocrine status in the estuarine killifish or mummichog (Fundulus heteroclitus macrolepidotus; northern subspecies). To evaluate if variations in salinity or temperature holding conditions modify the effects of EE₂ on gonad size, plasma reproductive steroid levels, and gonadal steroidogenesis, mummichog were exposed in vivo for 14 days to 0, 50 and 250 ng/L EE₂ in 0, 16 and 32 ppt salinity at 18°C and to 0 and 250 ng/L EE₂ at 10, 18 and 26°C at 16 ppt salinity. …

The Chronic Toxicity Of Titanium Dioxide Nanoparticles To The Freshwater Amphipod Hyalella Azteca, Gurkirpal S. Malhi

Theses and Dissertations (Comprehensive)

There has been an increased use of metal-oxide nanoparticles in both commercial and consumer products. The use of these products and waste generated during manufacture may ultimately be released into the aquatic environment and the potential for these contaminants to cause impacts must be assessed. This study examines the effect of titanium dioxide (TiO₂) nanoparticles (NPs) on Hyalella azteca. Chronic toxicity exposures were conducted in 400mL of spiked test solution and contained 20 neonates. Samples collected for characterization of Ti in TiO₂ NP exposure solutions were digested using ammonium persulfate as an oxidizing agent and dissolved …