Combinational Therapy to Mitigate α-Dicarbonyl Toxicity

<p>Diabetes mellitus is a metabolic disease characterized by hyperglycemia that affects 30 million children and adults in the United States alone. Patients suffering from diabetes have high concentrations of reactive α-dicarbonyls (α-DCs) like, methylglyoxal (MGO). The abundance of α-DCs form advanced glycation end products (AGEs); in turn, the accumulation of AGEs has been linked to secondary complications. Secondary complications include diabetic neuropathy, nephropathy and cardiomyopathy. A recently discovered TRPA-1-Nrf-2 pathway is a conserved mechanism in vertebrates and invertebrates that detoxifies α-DCs; however, regulators that activate the detoxification mechanism are currently unknown. Several supplement grade compounds were screened for TRPA-1-Nrf2 induced activity in <em>Caenorhabditis elegans</em>. The drug screen revealed several candidates that decreased methylglyoxal levels using the TRPA-1-Nrf-2 pathway. Regulatory mechanisms that trigger this detoxification pathway open up avenues for therapeutic studies. Candidates were utilized to determine their therapeutic efficacy in mammalian <em>in vitro</em> studies, in the background of methylglyoxal stress. In this work, we pursue combinational therapy to identify a more effective approach at mitigating neurotoxicity. We show that a five-compound combination ameliorates methylglyoxal stress in multiple dopaminergic cell lines: N27, PC12 and SH-SY5Y. Results indicate that combinational therapy counteracts methylglyoxal stress more effectively than compounds used in isolation. Data suggests that the five-compound mixture can be used as a potential supplement to treat diabetic complications in patients suffering from long term diabetes.</p>

Name thesis:degree_name

Master of Science

Level thesis:degree_level

Master's Thesis

Discipline thesis:degree_discipline

Biological Sciences

Year dc:date.available

2018

Author dc:creator

• Ramirez, Jessica

Contributors dc:contributor

• Pankah Kapahi, PhD
• Kiowa Bower, PhD

• Hyperglycemia
• Diabetes
• Medicine and Health Sciences

Repository record dc:identifier

https://scholar.dominican.edu/masters-theses/336

OAI identifier oai:identifier

oai:scholar.dominican.edu:masters-theses-1351