Date of Award
Summer 7-12-2023
Embargo Period
7-25-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Drug Discovery and Biomedical Sciences
College
College of Graduate Studies
First Advisor
Mark Hamann
Second Advisor
Yuri Peterson
Third Advisor
Nancy Demore
Fourth Advisor
David Turner
Fifth Advisor
Victoria Findlay
Abstract
Reactive Carbonyl Species (RCS) arise from the degradation of essential primary metabolites—sugars and lipids. The resulting stress, derived from their ability to spontaneously react with proteins, DNA, and monoamine neurotransmitters, is a fundamental biological pressure that has driven the evolution of diverse mechanisms for minimizing its impact on organismal health. Relevant to human health, the complications that accompany metabolic disorders, such as diabetes, illustrate what happens when RCS stress exceeds the body’s capacity to prevent excessive damage and the formation of the resulting Advanced Glycation End Products (AGE). These include elevated risks for cardiovascular disease, liver disease, kidney disease, neurodegeneration, and cancer, which are accompanied by a heightened vulnerability to infections. Presented here is a novel quantitative NMR technique for evaluating and screening natural products to discover scavengers of a prominent RCS, methylglyoxal. This tool was employed to explore the chemical diversity of marine macroalgae, with a focus on species that have a history in the diets of the World’s healthiest populations. The results revealed the exceptional RCS scavenging capacity and AGE formation inhibition of phlorotannins, a class of molecules unique to select Phaeophyte species. Likewise, the guanylureas an unusual class of alkaloids found in Rhodophytes, were found to possess similar activity of the diabetes front line therapy, metformin—evoking questions about their impact on the longevity of populations that regularly consume them. Finally, presented here is a hypothesis and supporting evidence for how RCS stress also drives the progression of diabetes and a new insight into the contested mechanism for metformin’s therapeutic effect. Both implicate the dynamic role of gamma-aminobutyric acid (GABA) as a signaling molecule in the pancreas—which is susceptible to depletion by methylglyoxal. This leads to the formation of a methylglyoxal-GABA-derived AGE, MOGD, described here for the first time. This discovery offers direction for future research into the effect RCS stress has on the dynamic biological processes that involve monoamine neurotransmitters.
Recommended Citation
Hanna, George, "Marine Macroalgae Derived Natural Product Inhibitors of Advanced Glycation End Product Formation by Scavenging of Reactive Carbonyl Species and their Implications in Slowing the Progression of Prevalent Chronic Diseases" (2023). MUSC Theses and Dissertations. 809.
https://medica-musc.researchcommons.org/theses/809
Rights
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