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- All Subjects: Bexarotene
- All Subjects: Aging
- All Subjects: Zika Virus
- Creators: Hackney Price, Jennifer
- Member of: Barrett, The Honors College Thesis/Creative Project Collection
- Member of: Theses and Dissertations
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
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
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