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- Creators: Debussy, Claude, 1862-1918
- Status: Published
ContributorsDebussy, Claude, 1862-1918 (Composer)
ContributorsDebussy, Claude, 1862-1918 (Composer)
ContributorsDebussy, Claude, 1862-1918 (Composer)
ContributorsDebussy, Claude, 1862-1918 (Composer)
ContributorsDebussy, Claude, 1862-1918 (Composer)
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 is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.
ContributorsYang, Joanna (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Hibler, Elizabeth (Committee member) / Barrett, The Honors College (Contributor)
Created2012-05
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