Medicine and Health Sciences Commons^™

Rna Nanotechnology For Next Generation Targeted Drug Delivery, Fengmei Pi

Theses and Dissertations--Pharmacy

The emerging field of RNA nanotechnology is developing into a promising platform for therapeutically application. Utilizing the state-of-art RNA nanotechnology, RNA nanoparticles can be designed and constructed with controllable shape, size for both RNA therapeutics and chemical drug delivery. The high homogeneity in particle size and ease for RNA therapeutic module conjugation, made it feasible to explore versatile RNA nanoparticle designs for preclinical studies.

One vital module for therapeutic RNA nanoparticle design is RNA aptamer, which can enable the RNA nanoparticles find its specific target for targeted drug delivery. A system of screening divalent RNA aptamers for cancer cell targeting …

The Role Of Pxr And Ikkβ Signaling In Cardiometabolic Disease, Robert N. Helsley

Theses and Dissertations--Pharmacology and Nutritional Sciences

Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive. …

Understanding Dna Condensation By Low Generation (G0/G1) And Zwitterionic G4 Pamam Dendrimers, Min An

Theses and Dissertations--Chemistry

Cationic polymers have shown potential as gene delivery vectors due to their ability to condense DNA and protect it from cellular and restriction nucleases. Dendrimers are hyperbranched macromolecules with precisely defined molecular weights and highly symmetric branches stemming from a central core. The nanosize, tunable surface chemistries and ease of surface functionalization has made dendrimers an attractive alternative to conventional linear polymers for DNA delivery applications. The commercially available, cationic dendrimer poly(amidoamine) or PAMAM is the most widely studied dendrimer for use as a gene delivery vector. The aim of this dissertation is to provide an increased understanding of the …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Target-Directed Biosynthetic Evolution: Redirecting Plant Evolution To Genomically Optimize A Plant’S Pharmacological Profile, Dustin Paul Brown

Theses and Dissertations--Neuroscience

The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity …

Lipid Extraction From Scenedesmus Sp. Microalgae For Biodiesel Production Using Hot Compressed Hexane, Hee-Yong Shin, Jae-Hun Ryu, Seong-Youl Bae, Czarena L. Crofcheck, Mark Crocker

Center for Applied Energy Research Faculty and Staff Publications

Lipid extraction from Scenedesmus sp. microalgae using hot compressed hexane (HCH) was investigated. Extraction performance was evaluated near the critical point of hexane and was compared with that of hexane extraction performed at room temperature and pressure, and the Bligh and Dyer extraction method. Experimental data showed that HCH significantly improves the lipid yield and rate of lipid extraction compared to the use of hexane at ambient conditions. High yields of biodiesel-convertible lipid fractions were rapidly achieved at the critical point of hexane, at a level comparable to that of the Bligh and Dyer method.

Effects Of Sodium Hydroxide Pretreatment On Structural Components Of Biomass, Alicia A. Modenbach, Sue E. Nokes

Biosystems and Agricultural Engineering Faculty Publications

Pretreatment is a unit operation in the conversion of biomass to valuable products that utilizes various combinations of conditions, including chemicals, heat, pressure, and time, to reduce the recalcitrance of lignocellulose. Many such pretreatments have been developed over the years, as the operating conditions can be adapted so that lignocellulose is modified in ways unique to each pretreatment. By tailoring pretreatment conditions to achieve these modifications, the types of final products produced can be controlled. The purpose of this review is to provide a consolidated source of information for sodium hydroxide effects on lignocellulose. The structural characteristics of lignocellulose and …

Investigating Structure And Protein-Protein Interactions Of Key Post-Type Ii Pks Tailoring Enzymes, Theresa E. Downey

Theses and Dissertations--Pharmacy

Type II polyketide synthase (PKS) produced natural products have proven to be an excellent source of pharmacologically relevant molecules due to their rich biological activities and chemical scaffolds. Type II-PKS manufactured polyketides share similar polycyclic aromatic backbones leaving their diversity to stem from various chemical additions and alterations facilitated by post-PKS tailoring enzymes. Evidence suggests that post-PKS tailoring enzymes form complexes in order to facilitate the highly orchestrated process of biosynthesis. Thus, protein-protein interactions between these enzymes must play crucial roles in their structures and functions. Despite the importance of these interactions little has been done to study them. In …

Synthesis And Biological Evaluation Of Novel Resveratrol And Combretastatin A4 Derivatives As Potent Anti-Cancer Agents, Nikhil Reddy Madadi

Theses and Dissertations--Pharmacy

Resveratrol has been reported as a potential anticancer agent but cannot be used as an antitumor drug due to its chemical and metabolic instability. We have designed and synthesized 184 novel compounds related to resveratrol in an attempt to produce more potent and drug-like molecules. We have identified a tetrazole analog of resveratrol, ST-145(a) as a lead anticancer agent from the resveratrol analog series of compounds with a GI₅₀ value of less than 10nM against almost all the human cancer cell lines in the National Cancer Institute’s screening panel.

In a separate study, we tested the hypothesis that the …

Bioerodible Calcium Sulfate Bone Grafting Substitutes With Tailored Drug Delivery Capabilities, Bryan R. Orellana

Theses and Dissertations--Biomedical Engineering

Bone regeneration or augmentation is often required prior to or concomitant with implant placement. With the limitations of many existing technologies, a biologically compatible synthetic bone grafting substitute that is osteogenic, bioerodible, and provides spacing-making functionality while acting as a drug delivery vehicle for bioactive molecules could provide an alternative to ‘gold standard’ techniques.

In the first part of this work, calcium sulfate (CS) space-making synthetic bone grafts with uniformly embedded poly(β-amino ester) (PBAE) biodegradable hydrogel particles was developed to allow controlled release of bioactive agents. The embedded gel particles’ influence on the physical and chemical characteristics of CS was …

Quantification Of Factors Governing Drug Release Kinetics From Nanoparticles: A Combined Experimental And Mechanistic Modeling Approach, Kyle Daniel Fugit

Theses and Dissertations--Pharmacy

Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies.

A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release …

Attenuating Trigeminal Neuropathic Pain By Repurposing Pioglitazone And D-Cycloserine In The Novel Trigeminal Inflammatory Compression Mouse Model, Danielle N. Lyons

Theses and Dissertations--Physiology

Approximately 22% of the United States population suffers from a chronic orofacial pain condition. One such condition is known as trigeminal neuropathic pain frequently reported as continuous aching and burning pain, often accompanied by intermittent electrical shock-like sensations. Dental procedures or trauma are known causes of peripheral trigeminal nerve injury and inflammation. Patients who have this type of facial pain also suffer from emotional distress. For these reasons, trigeminal neuropathic pain needs to be studied in more detail to improve the understanding of the etiology and maintenance of this condition, as well as to develop effective treatment strategies. The first …

Valproic Acid Causes Proteasomal Degradation Of Dicer And Influences Mirna Expression, Zhaiyi Zhang, Paolo Convertini, Manli Shen, Xiu Xu, Frédéric Lemoine, Pierre De La Grange, Douglas A. Andres, Stefan Stamm

Molecular and Cellular Biochemistry Faculty Publications

Valproic acid (VPA) is a commonly used drug to treat epilepsy and bipolar disorders. Known properties of VPA are inhibitions of histone deacetylases and activation of extracellular signal regulated kinases (ERK), which cannot fully explain VPA's clinical features. We found that VPA induces the proteasomal degradation of DICER, a key protein in the generation of micro RNAs. Unexpectedly, the concentration of several micro RNAs increases after VPA treatment, which is caused by the upregulation of their hosting genes prior to DICER degradation. The data suggest that a loss of DICER protein and changes in micro RNA concentration contributes to the …

Enzymatic Hydrolysis Of Biomass At High-Solids Loadings – A Review, Alicia A. Modenbach, Sue E. Nokes

Biosystems and Agricultural Engineering Faculty Publications

Enzymatic hydrolysis is the unit operation in the lignocellulose conversion process that utilizes enzymes to depolymerize lignocellulosic biomass. The saccharide components released are the feedstock for fermentation. When performed at high-solids loadings (≥ 15% solids, w/w), enzymatic hydrolysis potentially offers many advantages over conversions performed at low- or moderate-solids loadings, including increased sugar and ethanol concentrations and decreased capital and operating costs.

The goal of this review is to provide a consolidated source of information on studies using high-solids loadings in enzymatic hydrolysis. Included in this review is a brief discussion of the limitations, such as a lack of available …

Biosynthetic Pathway Of The Aminoribosyl Component Of Lipopeptidyl Nucleoside Antibiotics, Xiuling Chi

Theses and Dissertations--Pharmacy

Several lipopeptidyl nucleoside antibiotics that inhibit bacterial translocase I (MraY) involved in peptidoglycan cell wall biosynthesis contain an aminoribosyl moiety, an unusual sugar appendage in natural products. A-90289 and muraminomicin are the two representative antibiotics that belong to this family. Bioinformatic analysis of the biosynthetic A-90289 gene clusters revealed that five enzymes are likely involved in the assembly and attachment of the aminoribosyl unit. These enzymes of A-90289 are functionally assigned by in vitro characterization. The results reveal a unique ribosylation pathway that highlighted by uridine-5′-monophosphate as the source of the sugar, a phosphorylase strategy to generate a sugar-1-phosphate, and …

The Mesocorticolimbic Dopamine Pathway Reconstituted In Vitro: Glutamate Receptors And Corticosteroid-Methamphetamine Neurotoxicity, Jennifer N. Berry

Theses and Dissertations--Psychology

Stress promotes the use of methamphetamine and other recreational substances and is often implicated in relapse to stimulant use. Thus, it is of critical importance to examine the consequences of the co-occurance of stress and methamphetamine use. Activity of the glutamatergic N-methyl D-aspartate (NMDA) receptor system appears to be involved in the neurotoxic effects of both chronic stress and methamphetamine exposure. The current studies investigated the hypothesis that chronic pre-exposure to the stress hormone corticosterone (CORT) results in an increase of NMDA receptor activity and that this will potentiate the neurotoxic effects of methamphetamine (METH). Co-cultures of the …

A Novel Selective Lipid Uptake Pathway Contributing To Ldl-Induced Macrophage Foam Cell Formation, Jason M. Meyer

Theses and Dissertations--Molecular and Cellular Biochemistry

Atherosclerosis is a disease characterized by cholesterol-rich plaques within the intima of medium and large arteries. Cholesterol deposition is thought to occur by infiltration of low-density lipoprotein (LDL) into lesions followed by uptake into macrophages, generating lipid-loaded “foam cells.” Foam cells can also be generated in vitro by treatment of macrophages with LDL or oxidized LDL (oxLDL). The purpose of the current investigation was to determine the contribution of selective cholesteryl ester (CE) uptake versus whole-particle uptake during LDL-induced foam cell formation in cultured macrophages. Murine bone marrow-derived macrophages (BMMs) exhibited significant cholesterol accumulation when treated with LDL as indicated …

Synthesis And Stability Studies Of Prodrugs And Codrugs Of Naltrexone And 6-Β-Naltrexol, Joshua A. Eldridge

Theses and Dissertations--Pharmacy

The present study was divided between two different drug delivery goals, each involving naltrexone (NTX) or its active metabolite, 6-β-naltrexol (NTXOL). First, amino acid esters of NTX and NTXOL were prepared in order to test their candidacy for microneedle-enhanced transdermal delivery. Second, a 3-O-(-)-cytisine-naltrexone (CYT-NTX) codrug was prepared for screening as a potential oral delivery form of NTX and (-)-cytisine (CYT). The amino acid prodrugs were intended for the treatment of alcohol abuse, while the codrug was designed as a single agent for the treatment of alcoholism and tobacco-dependency co-morbidities. One hypothesis of this work was that prodrugs …

Effects Of Intranasally Administered Dnsp-11 On The Central Dopamine System Of Normal And Parkinsonian Fischer 344 Rats, James H. Sonne

Theses and Dissertations--Neuroscience

Due to the blood-brain barrier, delivery of many drugs to the brain has required intracranial surgery which is prone to complication. Here we show that Dopamine Neuron Stimulating Peptide 11 (DNSP-11), following non-invasive intranasal administration, protects dopaminergic neurons from a lesion model of Parkinson’s disease in the rat. A significant and dose-dependent increase in an index of dopamine turnover (the ratio of DOPAC to dopamine) was observed in the striatum of normal young adult Fischer 344 rats by whole-tissue neurochemistry compared to vehicle administered controls.

Among animals challenged with a moderate, unilateral 6-hydroxy-dopamine (6-OHDA) lesion of the substantia nigra, those …

Borrelia Burgdorferi Cp32 Bpab Modulates Expression Of The Prophage Nucp Nuclease And Ssbp Single-Stranded Dna-Binding Protein, Alicia M. Chenail, Brandon L. Jutras, Claire A. Adams, Logan H. Burns, Amy Bowman, Ashutosh Verma, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The Borrelia burgdorferi BpaB proteins of the spirochete's ubiquitous cp32 prophages are DNA-binding proteins, required both for maintenance of the bacteriophage episomes and for transcriptional regulation of the cp32 erp operons. Through use of DNase I footprinting, we demonstrate that BpaB binds the erp operator initially at the sequence 5′-TTATA-3′. Electrophoretic mobility shift assays indicated that BpaB also binds with high affinity to sites located in the 5′ noncoding regions of two additional cp32 genes. Characterization of the proteins encoded by those genes indicated that they are a single-stranded DNA-binding protein and a nuclease, which we named SsbP and NucP, …

Effects Of Methoprene On The Survivorship Of Adult Aedes Mosquitoes: A Strategy Or Inactivating Released Mosquitoes, Peter J. Brabant Iii

Theses and Dissertations--Entomology

Methoprene is a Juvenile Hormone (JH) analogue commonly used for the control of mosquito larvae. When applied to a mosquito breeding site, methoprene enters the haemolymph, where it mimics the function of JH and interferes with normal metamorphosis, resulting in larval mortality. Methoprene is commonly used for the control of larvae and has not been used as an adulticide, due to an absence of acute effects. This study evaluated possible chronic effects caused by the exposure of adult Aedes mosquitoes to methoprene. Methoprene was applied, in both technical grade and the commercially available Altosid®, topically to adults through droplet application …

Enantioselective Demethylation: The Key To The Nornicotine Enantiomeric Composition In Tobacco Leaf, Bin Cai

Theses and Dissertations--Plant and Soil Sciences

Nicotine and nornicotine are the two main alkaloids that accumulate in Nicotiana tabacum L. (tobacco), and nornicotine is the N-demethylation metabolite of nicotine. Nicotine is synthesized in the root, and probably primarily in the root tip. Both nicotine and nornicotine exist as two isomers that differ from each other by the orientation of H atom at the C-2' position on the pyrrolidine ring. (S)-nicotine is the dominant form in tobacco leaf and the enantiomer fraction of nicotine (EF_nic), the fraction of (R)-enantiomer over the total nicotine, is approximately 0.002. Despite considerable efforts to elucidate nicotine and nornicotine …

Multimeric Hemicellulases Facilitate Biomass Conversion, Zhanmin Fan, Kurt Wagschal, Wei Chen, Michael D. Montross, Charles C. Lee, Ling Yuan

Plant and Soil Sciences Faculty Publications

Two highly active trifunctional hemicellulases were constructed by linking the catalytic portion of a xylanase with an arabinofuranosidase and a xylosidase, using either flexible peptide linkers or linkers containing a cellulose-binding domain. The multifunctional enzymes retain the parental enzyme properties and exhibit synergistic effects in hydrolysis of natural xylans and corn stover.

A Case-Control Study Of Farming And Prostate Cancer In African-American And Caucasian Men, Tamra E. Meyer, Ann L. Coker, Maureen Sanderson, Elaine Symanski

CRVAW Faculty Journal Articles

Objective: To determine the risk of prostate cancer associated with farming by duration, recency and specific activities among African-Americans and Caucasians.

Methods: This population-based case–control study had information on farming-related activities for 405 incident prostate cancer cases and 392 controls matched for age, race and region in South Carolina, USA, from 1999 to 2001. Cases with histologically confirmed, primary invasive prostate cancer who were aged between 65 and 79 years were ascertained through the South Carolina Central Cancer Registry. Appropriately matched controls were identified from the Health Care Financing Administration Medicare Beneficiary File. Data were collected using computer-assisted telephone interviewing, …

Optimization Of Solid-State Fermentation Parameters For The Production Of Xylanase By Trichoderma Longibrachiatum On Wheat Bran In A Forced Aeration System, Elizabeth R. Ridder, Sue E. Nokes, Barbara L. Knutson

Biosystems and Agricultural Engineering Faculty Publications

The effect of aeration on the production of xylanase by Trichoderma longibrachiatum on wheat bran in a solid-state fermentation (SSF) system has not been investigated. This study was conducted to investigate the interactive effects of aeration, initial moisture content of the substrate, and depth of the substrate on xylanase activity produced in a tray fermenter. The experiment was conducted as a split plot experiment with factorial treatments and three replications of each treatment combination. The whole plot treatment was aeration rate (0, 2.9, 5.7 L/min/kg bran). Initial moisture content (45, 55, 65% w.b.) and depth of substrate (1.0 and 2.5 …

Optimization Of Solid-State Fermentation Parameters For The Production Of Xylanase By Trichoderma Longibrachiatum On Wheat Bran, Elizabeth R. Ridder, Sue E. Nokes, Barbara L. Knutson

Biosystems and Agricultural Engineering Faculty Publications

Solid-state fermentation has the potential to produce inexpensive enzymes for use in high-volume industrial applications. Process parameters such as substrate moisture content and length of fermentation can have a significant effect on the amount and timing of enzyme production. This study was conducted in two stages, a screening stage and an optimization stage, to determine the effects of moisture content of the substrate, surfactant addition upon inoculation, depth of the substrate, and duration of fermentation on xylanase activity produced by Trichoderma longibrachiatum. Screening fermentations were conducted at 25°C, 50 and 75% wet basis moisture content (w.b.), 0.0 and 0.2% …

The Aquatic Toxicity Of Organic Compounds To Embryo-Larval Stages Of Fish And Amphibians, Jeffrey A. Black, Wesley J. Birge, Willaim E. Mcdonnell, Albert G. Westerman, Barbara A. Ramey, Donald M. Bruser

KWRRI Research Reports

Aquatic toxicity tests were conducted on 11 organic compounds considered hazardous to water resources. The toxicity of each compound was evaluated using embryo-larval stages of two to eight fish and amphibian species. Exposure was initiated at fertilization and maintained through 4 days posthatching. The animal test species exhibited varying degrees of sensitivity to the selected toxicants. Combined frequencies for mortality and teratogenesis at 4 days posthatching gave LC₅₀ ranges of 3.66 to 8.25 mg/L for benzene, 1.16 to 22.42 mg/L for carbon tetrachloride, 0.11 to 1.20 mg/L for chlorobenzene, 2.03 to > 68 mg/L for chloroform, 3.01 to 5.56 mg/L …

Low Pressure Membrane Separation Process To Remove Heavy Metal Complexes, Dibakar Bhattacharyya, Chin-Shun Cheng

KWRRI Research Reports

The overall objective of this investigation is to establish the rejection behavior of heavy metals in the presence of complexing agents, utilizing negatively charged ultrafiltration membranes. An extensive experimental investigation is conducted with Zn²⁺, Cd²⁺, Cu²⁺, and Cu¹⁺ in the presence of cyanide, ethylenediamine tetraacetic acid, and oxalates, under insignificant concentration polarization condition. The rejection dependence of the heavy metals is found to be a function of feed metal concentration, metal types, complexing agent to metal feed molar ratio, pH and ionic strength. The dependence of rejection behavior of heavy metals and complexing …

An Avoidance Response Bioassay For Aquatic Pollutants, Jeffrey A. Black, Wesley J. Birge

KWRRI Research Reports

Avoidance response bioassays were conducted with eight aquatic contaminants, including cadmium, copper, mercury, zinc, chloroform, dioctyl phthalate (DOP), trisodium nitrilotriacetic acid (NTA), and phenol. Tests were performed in a dual-channel fluviarium system, and the toxicant injection procedure used provided good regulation of exposure concentrations. Juvenile stages of largemouth bass (Micropterus salmoides), bluegill sunfish (Lepomis macrochirus), and rainbow trout (Salmo gairdneri), and tadpoles of the American toad (Bufo americanus) proved to be suitable animals for evaluating avoidance or attraction responses. The trout was the most sensitive species tested.

Avoidance was significant in tests …

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 …