Matching Items (12)
Description
Vitamin D, a bioactive lipid and essential nutrient, is obtained by humans through either endogenous synthesis in response to UV light exposure or via nutritional intake. Once activated to its hormonal form, vitamin D binds to and activates the nuclear vitamin D receptor (VDR). Activation of VDR is known to modulate gene transcription in vitamin D target tissues such as kidney, colon, and bone; however, less is known about the ability of VDR to respond to "nutritional modulators". One such potential VDR modulator is resveratrol, a plant-derived polyphenol and potent antioxidant nutrient that also functions as a chemopreventative. Resveratrol is known to activate sirtuin-1, a deacetylase enzyme with potential anti-aging properties. This study explores the potential for resveratrol, an anticancer nutraceutical, to upregulate VDR activity through its effector protein, sirtuin-1. Furthermore, due to its putative interactions with several intracellular signaling pathways, klotho has been proposed as an anti-aging protein and tumor suppressor gene, while the Wnt/β-catenin signaling pathway drives enhanced cellular proliferation leading to numerous types of cancers, especially colorectal neoplasia. Thus, the ability of klotho to cooperate with vitamin D to inhibit oncogenic β-catenin signaling was also analyzed. The experiments and resultant data presented in this thesis explore the potential role of VDR as a physiologically relevant nutritional sensor in human cells. This novel study reveals the importance of nutrient modulation of the VDR system by vitamin D and resveratrol and how this might represent a molecular mechanism that is responsible for the putative anti-cancer actions of vitamin D. Furthermore, this study enhances our understanding of how vitamin D/VDR and resveratrol interact with klotho and how this interaction affects β-catenin signaling to mitigate oncogenic growth and differentiation. This works demonstrates that the vitamin D hormone serves as a likely chemopreventive agent for various types of cancers through control of anti-oxidation and cellular proliferation pathways via its nuclear receptor. Our results also indicate the potential for resveratrol, an anticancer nutraceutical, to upregulate VDR activity through SIRT1. Furthermore, the novel data presented in this work illustrate that klotho, an anti-aging protein, cooperates with vitamin D to synergistically inhibit oncogenic β-catenin signaling. Ultimately, this study enhances our understating of the molecular pathways that underpin nutritional chemoprevention, and how modulation of these pathways via dietary intervention may lead to advances in public health strategies to eventually curb carcinogenesis.
ContributorsKhan, Zainab (Author) / Jurutka, Peter (Thesis director) / Hackney Price, Jennifer (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Rainbowfish, Melanotaenia splendida, are a common freshwater species in tropical regions of the world. They are members of the Atheriniformes (Atherinomorpha), the silverside fishes, which are known for some unusual feeding behaviors. Their close relatives, the Cypriniformes, such as mollies, guppies, and mosquitofish, are well studied and exhibit innovative morphologies associated with feeding. The third member of the Atherinomorphs, the Beloniformes, contains the recognizably odd needlefish, halfbeaks, and flying fishes. As a group, it is fair to say that the Atherinomorpha contain some pretty unusual fishes. The purpose of this project was to gain a further understanding of the unique feeding kinematics of Atheriniform fishes using the rainbowfish as an exemplar species. Feeding kinematics were quantified using high speed video recording unrestrained feeding events. Three feeding events from five individuals were analyzed frame by frame, from the time of the mouth opening to mouth closing. The X,Y coordinates of seven specific points were used to calculate the following kinematic variables: cranial elevation, gape distance, premaxillary protrusion, and hyoid depression. The contribution of cranial elevation to the strike was inconsistent. At times the fish raised the head as they expanded the mouth for prey capture, and at other times they did not. Cranial elevation is theoretically important for expanding the head during suction prey capture. Hyoid depression was more consistent, and clearly contributed to expansion of the head elements. Premaxillary protrusion contributed strongly to the event, and the jaws are closed with the premaxilla still protruded, facilitating a ‘nipping’ style jaw closure. A nipping style of prey capture is much like the Cyprinodontiforms, however, in rainbowfish, the event was quicker, and appeared to rely heavily on suction. We used both cleared and stained specimens and CT scans to investigate the underlying morphology of rainbowfish. These images revealed nearly microscopic teeth on the exterior of the jaws, and other features associated with feeding on highly elusive prey (i.e. prey that are mobile and likely to be able to escape predation). Further examination revealed a surprisingly well developed set of pharyngeal jaws, secondary to the oral jaws. The structure of the pharyngeal jaws suggested that most of the prey processing occurred within the pharynx.
ContributorsLerma, Sarahi (Author) / Ferry, Lara A. (Thesis director) / Hackney Price, Jennifer (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor) / School of Social and Behavioral Sciences (Contributor)
Created2015-05
Description
Bexarotene (Bex) is a FDA-approved drug used to treat cutaneous T-cell lymphoma (CTCL). It binds with high affinity to the retinoid-X-receptor (RXR), a nuclear receptor implicated in numerous biological pathways. Bex may have the potential to attenuate estrogenic activity by acting as an estrogen receptor alpha (ERα) signaling antagonist, and can therefore be used to treat ERα-positive cancers, such as breast cancer. Using dual luciferase reporter assays, real-time qRT-PCR, and metabolic proliferation assays, the anti-estrogenic properties of Bex were ascertained. However, since Bex produces numerous contraindications, select novel RXR drug analogs were also evaluated. Results revealed that, in luciferase assays, Bex could significantly (P < 0.01) inhibit the transcriptional activity of ERα, so much so that it rivaled ER pan-antagonist ZK164015 in potency. Bex was also able to suppress the proliferation of two breast cancer cell models, MCF-7 and T-47D, and downregulate the expression of an estrogen receptor target gene (A-myb), which is responsible for cell proliferation. In addition, novel analogs A30, A33, A35, and A38 were evaluated as being more potent at inhibiting ERE-mediated transcription than Bex at lower concentrations. Analogs A34 and A35 were able to suppress MCF-7 cell proliferation to a degree comparable to that of Bex. Inhibition of T-47D cell proliferation, by contrast, was best achieved by analogs A34 and A36. For those with ERα – positive breast cancer who are refractory to current chemotherapeutics used to treat breast cancer, Bex and its analogs may prove to be useful alternative options.
ContributorsBains, Supreet (Author) / Jurutka, Peter (Thesis director) / Hackney Price, Jennifer (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Colchicine is a chemical known for inhibiting mitosis during eukaryotic cellular reproduction by halting the tubulin formation necessary for the division of the chromosomes. The meristem is the primary source of mitosis in developing flowering plants, and it was the focus of our research to determine if the hindrance of mitosis would interfere with the production of capsaicinoids within pungent pepper plants. Moruga Scorpion peppers have one of the world's highest concentration of capsaicinoids with Scoville Heat Units (SHU) averaging 1.2 million SHU (Bannister, 2012). The highest concentration of these capsaicinoids are within the placental and endocarp regions of the fruit, which are the primary location for capsaicinoid biosynthesis (Aza-Gonzalez & Nunez-Palenius, 2010). Hindering mitosis from the earliest stage of development could lead to phenotypic abnormalities within those placental and endocarp regions, quite possibly through the mechanism of the induced polyploidy. In many cases, this polymerization interference is beneficial in cultivating plants with characterized polyploidy due to its desired increased size of fruits and leaves. Due to the lethal nature of colchicine, there is threshold of effectiveness where it may induce polyploidy or it may result in fatality. This first stage of this research sought to determine which lethal dose was required to elicit a polyploid response or lead to seed unviability. The second stage was analyzing capsaicin concentration within the fruit of the mature dosed plants to determine whether there was an effect on the capsaicinoids, and whether polyploidy played a role in those effects. The final inspection of this research was in germinating the seeds from the hottest F1 pepper that had developed the fruit the slowest of all the doses, and determining whether there were any effects on the germination or seedling development.
ContributorsKeppler, Lydia Jacqueline (Author) / Cahill, Thomas (Thesis director) / Sweat, Ken G. (Committee member) / Hackney Price, Jennifer (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The significance of hormonal vitamin D in the numerous facets of health stresses the importance of elucidating the molecular mechanism(s) associated with 1,25D-VDR signaling modulators (e.g., resveratrol and sirtuin-1). Resveratrol (Res), a natural antioxidant, is a potent activator of NAD-dependent deacetylase sirtuin-1 (SIRT-1), an enzyme associated with longevity in animal models. This present study employed mammalian 2-hybrid (M2H) and vitamin D responsive element (VDRE)-based transcriptional assays to investigate the potential effects of Res and SIRT-1 on VDR signal transduction. Results from VDRE-based assays indicate that Res and SIRT-1 potentiate 1,25D-VDR activity via cell-and-promoter-specific pathways. In addition, 1,25D displacement experiments revealed an increase in VDR-bound radiolabeled 1,25D in the presence of Res, suggesting that Res may potentiate VDR transactivation by stimulating 1,25D binding. M2H assays in HEK293 cells were then utilized to assess levels of interaction between VDR and VDR comodulators, including RXR, SRC-1, and DRIP-205. Both Res and SIRT-1 increased the ability of VDR to associate with RXR; however, SRC-1 and DRIP-205 interactions were not enhanced. The activity of a novel, non-acetylatable VDR mutant, K413R, was probed revealing that K413R possesses amplified transactivation capacity over wild-type VDR. A SIRT-1 inhibitor, EX-527, was used to suppress endogenous SIRT-1, resulting in significantly decreased VDR transactivation. Finally, qPCR results in HEK293 cells revealed that the 1,25D-mediated induction of CYP24A1, an endogenous VDR target gene, was enhanced (85%) by SIRT-1 while Res increased CYP24A1 expression by 294%. The combination of 1,25D, SIRT-1, and Res amplified CYP24A1 expression by 326% over 1,25D, although this effect did not reach statistical significance when compared to the Res only treated group. We conclude that acetylation of VDR comprises a negative feedback loop that attenuates 1,25D-VDR signaling. This loop is suppressed by resveratrol/SIRT-1-catalyzed deacetylation of VDR, restoring VDR activity. The two compounds, 1,25-dihydroxyvitamin D (1,25D, vitamin D) and 5-hydroxytryptamine (5-HT, serotonin), have been proposed to play a significant role in abnormal social behavior associated with psychological conditions including autism spectrum disorders (ASDs) and depression; however, the mechanism underlying these associations has yet to be elucidated. Deficiencies in 1,25D or 5-HT have been linked to the increased incidence of ASDs. Thus, examining the modulation of genes involved in 5-HT biosynthesis, reuptake, and degradation is fundamental in linking low 1,25D levels to the increased incidence of psychiatric disorders. We propose that 1,25D regulates tryptophan hydroxylase-2 (TPH2), the initial and rate-limiting enzyme in the biosynthetic pathway of 5-HT. In order to evaluate the regulation of TPH2 in neuronal cells, three formulations of media were examined to optimize the cell culture conditions necessary for growth and morphology of embryonic rat medullary raphe (B14) serotonergic neurons. Next, quantitative real time-PCR (qPCR) was utilized to examine TPH2 expression in cultured human glioblastoma (U-87) cells and rat serotonergic neurons (B-14). Human TPH2 mRNA in U-87 cells was induced dose-dependently resulting in a 2.4-fold increase at 10 nM 1,25D. Strikingly, TPH2 mRNA in B-14 cells was observed to be 26- to 86-fold upregulated at 10 nM 1,25D; however, 1 nM and 100 nM 1,25D elicited significantly smaller inductions (8-fold and 1.2-fold, respectively).
ContributorsSabir, Marya Sabah (Author) / Jurutka, Peter (Thesis director) / Hackney Price, Jennifer (Committee member) / Sandrin, Todd R. (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2015-12
Description
Proper developmental fidelity ensures uninterrupted progression towards sexual maturity and species longevity. However, early development, the time-frame spanning infancy through adolescence, is a fragile state since organisms have limited mobility and responsiveness towards their environment. Previous studies have shown that damage during development leads to an onset of developmental delay which is proportional to the extent of damage accrued by the organism. In contrast, damage sustained in older organisms does not delay development in response to tissue damage. In the fruit fly, Drosophila melanogaster, damage to wing precursor tissues is associated with developmental retardation if damage is sustained in young larvae. No developmental delay is observed when damage is inflicted closer to pupariation time. Here we use microarray analysis to characterize the genomic response to injury in Drosophila melanogaster in young and old larvae. We also begin to develop tools to examine in more detail, the role that the neurotransmitter dopamine might play in mediating injury-induced developmental delays.
ContributorsContreras Rodriguez, Jesus (Co-author) / Lupone, Teresa (Co-author) / Beckett, Chaz (Co-author) / Almajan, Ashley (Co-author) / Leek, Ty (Co-author) / Hussain, Sabahat (Co-author) / Marsh, Tyler (Co-author) / Broatch, Jennifer (Co-author) / Hackney Price, Jennifer (Thesis director) / Sandrin, Todd (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
The elongases of very long chain fatty acid (ELOVL or ELO) are essential in the biosynthesis of fatty acids longer than C14. Here, two ELO full-length cDNAs (TmELO1, TmELO2) from the yellow mealworm (Tenebrio molitor L.) were isolated and the functions were characterized. The open reading frame (ORF) lengths of TmELO1 and TmELO2 were 1005 bp and 972 bp, respectively and the corresponding peptide sequences each contained several conserved motifs including the histidine-box motif HXXHH. Phylogenetic analysis demonstrated high similarity with the ELO of Tribolium castaneum and Drosophila melanogaster. Both TmELO genes were expressed at various levels in eggs, 1st and 2nd instar larvae, mature larvae, pupae, male and female adults. Injection of dsTmELO1 but not dsTmELO2 RNA into mature larvae significantly increased mortality although RNAi did not produce any obvious changes in the fatty acid composition in the survivors. Heterologous expression of TmELO genes in yeast revealed that TmELO1 and TmELO2 function to synthesize long chain and very long chain fatty acids.
ContributorsZheng, Tianxiang (Author) / Li, Hongshuang (Author) / Han, Na (Author) / Wang, Shengyin (Author) / Hackney Price, Jennifer (Author) / Wang, Minzi (Author) / Zhang, Dayu (Author) / New College of Interdisciplinary Arts and Sciences (Contributor)
Created2017-09-08
Description
Pollution causes many health problems in the modern world and the desert climates struggle with pollution in unique ways. In the Sonoran Desert, the research was conducted with the purpose of expanding the knowledge of the topic in this area. A literature review was conducted based on air, soil and noise pollution in the region. The Sonoran Desert has high levels of carcinogenic elements along with other pollutants due to the main industries of mining, agriculture and manufacturing. Overall, these findings show people in desert climates deal with high levels of pollutants.
ContributorsWest, Katherine (Author) / Hackney Price, Jennifer (Thesis director) / Savalli, Udo (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2023-05
Description
A long personal struggle with Lyme disease prompted me to review the current literature to better understand what remains elusive to researchers and physicians. Lyme disease was first discovered in Connecticut in the mid-1970’s, however, in Europe, it was already being treated with antibiotics. The disease is caused by a spirochete bacteria named Borrelia burgdorferi after the scientist who married the European syndromes associated with the microbe to the disease found in the United States. Borrelia burgdorferi is capable of evading the immune system through a variety of methods, some of which are still not clearly understood. Treatment for Lyme disease is effective and involves antibiotics over a variable duration depending on the presentation of the disease. Post-treatment Lyme Disease Syndrome (PTLDS) is the heart of the controversy surrounding this disease as patients continue to have debilitating symptoms with no clear cause.
ContributorsBailey, Susan Caroline (Author) / Hackney Price, Jennifer (Thesis director) / Marshall, Pamela (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Since its isolation from a rhesus monkey in the Zika forest of Uganda in 1947, Zika virus (ZIKV) has spread into many parts of the world, causing major epidemics, notably in the Americas and some parts of Europe and Asia. The flavivirus ZIKV is primarily transmitted to humans via the bite of infectious adult female Aedes mosquitoes. In the absence of effective treatment or a safe and effective vaccine against the disease, control efforts are focused on effective vector management to reduce the mosquito population and limit human exposure to mosquito bites. The work in this thesis is based on the use of a mathematical model for gaining insight into the transmission dynamics of ZIKV in a population. The model, which takes the form of a deterministic system of nonlinear differential equations, is rigorously analyzed to gain insight into its basic qualitative features. In particular, it is shown that the disease-free equilibrium of the model is locally-asymptotically stable whenever a certain epidemiological quantity (known as the reproduction number, denoted by R0) is less than unity. The epidemiological implication of this result is that a small influx of ZIKV-infected individuals or vectors into the community will not generate a large outbreak if the anti-ZIKV control strategy (or strategies) adopted by the community can reduce and maintain R0 to a value less than unity. Numerical simulations of the model, using data relevant to ZIKV transmission dynamics in Puerto Rico, shows that a control strategy that solely focuses on killing immature mosquitoes (using highly efficacious larvicides) can lead to the elimination of ZIKV if the larvicide coverage (i.e., proportion of breeding sites treated with larvicides) is high enough (over 90%). Such elimination is also feasible using a control strategy that solely focuses on the use of insect repellents (as a means of personal protection against mosquito bites) if the coverage level of the insect repellent usage in the community is high enough (at least 70%). However, it is also shown that although the use of adulticides (i.e., using insecticides to kill adult mosquitoes) can reduce the reproduction number (hence, disease burden), it fails to reduce it to a value less than unity, regardless of coverage level. Thus, unlike with the use of larvicide-only or repellent-only strategies, the population-wide implementation of an adulticide-only strategy is unable to lead to ZIKV elimination. Finally, it is shown that the combined (integrated pest management) strategy, based on using all three aforementioned strategies, is the most effective approach for combatting ZIKV in the population. In particular, it is shown that even a moderately-effective level of this strategy, which entails using only 50% coverage of both larvicides and adulticides, together with about 45% coverage for a repellent strategy, will lead to ZIKV elimination. This moderately-effective combined strategy seems attainable in Puerto Rico.
ContributorsUrcuyo, Javier (Author) / Gumel, Abba (Thesis director) / Hackney Price, Jennifer (Committee member) / School of Mathematical and Natural Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2019-05