Masters Theses

Date of Award

12-2015

Degree Type

Thesis

Degree Name

Master of Science

Major

Chemistry

Major Professor

Shawn R. Campagna

Committee Members

Tessa R. Calhoun, Michael D. Best

Abstract

This work studies a variety of molecules and the systems they are involved in to further understand disease and treatment of diabetes mellitus, malaria, and castrate resistant prostate cancer. The first system studied, diabetes mellitus, involves synthesis of 5 different steroidal compounds, while the other two systems, malaria and castrate-resistant prostate cancer, apply mass spectrometric-based untargeted metabolomics to study both known metabolites and unknown spectral features.

Diabetes mellitus is a result of the dysfunction and death of islet beta cells caused by the transcription of pro-inflammatory cytokines resulting in reduced insulin secretion and uncontrollable blood glucose levels. Glucocorticoids can reduce inflammation at the transcriptional level preventing islet beta cell destruction and could be applied to aid in pancreatic transplants. Five glucocorticoids, 3 differently acylated mercapto hydrocortisone derivatives and 2 arylpyrazole mercapto hydrocortisone derivatives were synthesized and fully characterized to be used in bioassays to determine efficacy complementing previous work from our lab.1

Untargeted mass spectrometric based metabolomics, using ultra performance liquid chromatography with an Orbitrap mass spectrometer was applied to study both malaria and castrate-resistant prostate cancer. This allowed for the acquisition of full scan data so that known metabolites, as well as unknown spectral features can be used for metabolic pathway and statistical analyses.

Recently, resistance to malaria has been observed as being influenced by gut microbiota indicating an unknown metabolite(s) transported between tissues is responsible for this change. Using our untargeted mass spectrometric based metabolomics approach unknown features were analyzed for plasma, cecum and small intestine samples for resistant and susceptible mice infected with Plasmodium yoelii. Exhibiting large significant fold-changes in concentration between resistant and susceptible mice, 8 spectral features were identified, and molecular formulae determined by m/z and isotope analysis.

Zyflamend, a dietary supplement consisting of herbal and spice extracts in olive oil, when taken along with hormone depravation therapy has shown to reduce prostate cancer growth twice as fast as hormone depravation therapy alone.2 By applying our untargeted UPLC-MS based metabolomics, changes in metabolomes of both humans and mice either treated with Zyflamend or the control (olive oil only) are detected and compared.

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