Document Type

Dissertation - Open Access

Award Date

2020

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

First Advisor

Fathi Halaweish

Abstract

Diabetes mellitus (DM) is a metabolic disease characterized by high levels of blood glucose resulting from defects in insulin production or action. A world-wide increase in the diabetes rate is projected to reach pandemic levels over the next 10-20 years. Current data shows that high numbers of the population in Saudi Arabia suffer from diabetes and prediabetes. Non-traditional treatments of diabetes from medicinal plants has shown potential antidiabetic activity. A considerable percentage of the population still prefer or use medicinal plants as a treatment or supplement to traditional medicine. Cissus rotundifolia (family Vitaceae) is a known plant in southwestern Saudi Arabia used by people in the region to treat skin diseases, burns and diabetes. The chemical and biological characteristics of Cissus rotundifolia’s active compounds are unknown. The aim of this study to investigate the chemical and biological properties of this medicinal plant using bio-assay guided separation. Aqueous methanol extract of Cissus rotundifolia was fractionated by partitioning against hexane and ethyl acetate. Methanol, ethyl acetate and hexane extracts were then screened for antidiabetic activity using an alphaglycosidase assay at a concentration of 12.5-50 mg/ml. Methanol extract showed a significant alpha-glucosidase inhibition percent of 58-95%. Further, LC separation afforded six compounds isolated and characterized using 1H-NMR, 13C-NMR and 2DNMR. Two of the isolated compounds: 3 and 4 (1,4-dimethyl 2-hydroxybutanedioate and 3-hydroxy-4-methoxy-4-oxobutanoate, respectively) showed a significant inhibition of alpha-glycosidase enzyme in the range of 25% to 50% at a concentration range from 1.00 – 0.25 mg/ml. Also, since glucose uptake is considered one of the main pathways to control blood sugar levels, the fractions and the isolated compounds were investigated for their glucose uptake activity. Glucose uptake assay results showed that the ethyl acetate fraction has a significant uptake activity. The isolated compounds 3 and 4 showed increased of glucose uptake activity reach of 19 % and 25%, respectively, with Insulin used as the positive control. Structural similarities of isolated compounds to malate which is a main substrate of citric acid cycle, prompted us to build hypothesis that these compounds might interfere with gluconeogenesis process through inhibition of the citric acid cycle. Molecular modeling study of isolated compounds and their analogs targeting all enzymes involve in citric acid cycle was conducted to examine potential binding affinity of these compounds toward proteins in citric acid cycle. Docking study showed analogs S-2-aminosuccininamide (AN21), levulinic acid and isolated compound SAA4 exhibiting high affinity binding to the fumarase enzyme that plays an important role in citric acid cycle. Docking study clearly suggest compound SAA4 has potential inhibition of gluconeogenesis. In conclusion, this study authenticated that C. rotundifolia potential antidiabetic activity through inhibition of intestinal α-glucosidase, induction of glucose uptake activity and possible inhibition of gluconeogenesis.

Format

application/pdf

Number of Pages

143

Publisher

South Dakota State University

Rights

In Copyright - Educational Use Permitted
http://rightsstatements.org/vocab/InC-EDU/1.0/

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