Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


Nicole-Thesis (woodard.174@osu.edu).pdf (6.53 MB)

ETD Abstract Container

Abstract Header

Zebrafish in the Discovery of Potential Antidiabetic Natural Product Leads

Woodard, Nicole A
http://rave.ohiolink.edu/etdc/view?acc_num=osu1566137370387466

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
With an estimated 425 million adults with diabetes world-wide,1 type 2 diabetes is increasingly becoming associated with the words “epidemic” and “pandemic” in research and medical fields.1–9 Unfortunately, the therapeutic options for type 2 diabetes include lifestyle changes that meet with significant patient resistance, expensive drugs with undesirable administration routes, and often severe side effects. It is thus critical to find new agents with possible antidiabetic and hypoglycemic effects with fewer adverse reactions. Natural products research historically has been a successful approach for the discovery of new drugs and lead molecules for medicinal chemistry optimization efforts. This high rate of success may be due to the structural complexity and diversity of natural products. Additionally, as secondary metabolites that serve some biological purpose for their source organism, naturally products frequently possess a biologically interactive conformation or orientation for a receptor, protein, or other target of different organisms. The power of natural product extracts and compounds was thus an enticing source of potential antidiabetic leads for investigation toward drug discovery and development. A library of edible spices and a library of plant and fungal natural product compounds were evaluated for antidiabetic effects in a panel of in vitro assays associated with anti-inflammatory, hypoglycemic, and anti-glucogenic activity. Through bioactivity-guided isolation, four known compounds were isolated from mace (a spice from the same species as nutmeg, Myristica fragrans), and one compound from each library was selected for derivatization. The isolates, derivatives, and numerous fractions were evaluated through the panel of in vitro assays. However, type 2 diabetes is characterized by a lack of insulin sensitivity, and since hormone regulation in cell culture models of diabetes are extremely variable and limited, cell culture is not an ideal model of the in vivo condition. Therefore, an organism capable of digestive metabolism and hormone regulation was necessary to evaluate the potential of lead compounds and extracts. Although secondary metabolites are often excellent lead candidates due to their structural diversity and tendency toward bioactive conformations, they are often isolated in low yields. A small organism that affords druggable doses despite frequent shortage of material, as well as semi-high-throughput amenability for screening many diverse compounds and extracts, was selected for model development. Zebrafish (Danio rerio) are small animals with one of the simplest routes of administration for both diabetogenic and therapeutic agents. Wild-type zebrafish larvae were thus developed as a type 2 diabetes animal model to monitor the diabetes therapeutic potential of compounds and extracts. Isolated M. fragrans neolignans and a series of glycated 4-phenylcoumarins were identified as lead compounds through the in vitro panel of assays. To evaluate their potential antidiabetic activity and to probe possible hypoglycemic mechanisms of action, one compound was selected for derivatization from each structurally related family, and the derivatives were analyzed in the newly developed type 2 diabetic larval zebrafish model. Through immunoblot, the expression of metabolic enzymes and diabetes-relevant molecular targets from treated zebrafish were evaluated. From the spice library, treatment with a fennel extract exhibited hypoglycemic and anti-inflammatory effects in type 2 diabetic zebrafish. From the diverse library of natural products, a glycated 4-phenylcoumarin was derivatized and subsequently identified as a novel natural product derivative and potential anti-inflammatory agent. From M. fragrans, three natural product compounds were determined to have anti-inflammatory effects that require further evaluation. A new compound derivatized from one of the M. fragrans isolates (an 8,3’-neolignan ethyl carbonate derivative) was also identified as a potential anti-inflammatory agent. Moreover, a M. fragrans natural product exhibited an excellent hypoglycemic effect in diabetic larval zebrafish but did not act through the antidiabetic pathway targeted in the present study; thus, it is an excellent candidate for further evaluation as an antidiabetic drug lead that may or may not lead to the identification of a novel mechanism of action. Importantly, the establishment of a new, small, high-throughput-amenable, type 2 diabetic zebrafish model was optimized in the present study and will be an excellent tool for continuing investigation of the 4-phenylcoumarins, M. fragrans and derivatized neolignans, and further antidiabetic drug discovery and development.
Esperanza Carcache de Blanco (Advisor)
360 p.
Biochemistry; Chemistry; Pharmacy Sciences
Diabetes; inflammation; metabolism; zebrafish; natural products; pharmacognosy; medicinal chemistry; bioassay; model development; compound library; extracts

Recommended Citations

Citations

  • Woodard, N. A. (2019). Zebrafish in the Discovery of Potential Antidiabetic Natural Product Leads [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1566137370387466

    APA Style (7th edition)

  • Woodard, Nicole. Zebrafish in the Discovery of Potential Antidiabetic Natural Product Leads. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1566137370387466.

    MLA Style (8th edition)

  • Woodard, Nicole. "Zebrafish in the Discovery of Potential Antidiabetic Natural Product Leads." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1566137370387466

    Chicago Manual of Style (17th edition)

osu1566137370387466
695
© 2019, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.