The relationship between fructose consumption and metabolic diseases has drawn substantial attention in recent years. Dietary fructose consumption has climbed dramatically in the past 40 years, and this trend coincides with the prevalence of obesity and diabetes worldwide. In rodents, maternal obesogenic diets are associated with higher risks of metabolic derangement later in life whereas bitter melon (BM) supplementation has been shown to improve blood glucose and lipid profiles. The overall objective of this thesis was to test the hypothesis that through developmental programming metabolic derangement in offspring born to rat dams fed a high-fructose (F) diet could be offset by the addition of BM to the maternal diet. Virgin female rats received a control (C), F (60%) or BM-supplemented F (FBM,1%) diet 8 weeks before conception and throughout gestation and lactation. Weaned male offspring consumed C diet (C/C,F/C,FBM/C) for 11 weeks. The concentrations of serum insulin, triglyceride, free fatty acid (FFA), and hepatic lipids in FBM/C offspring matched that in C/C offspring and were significantly lower than F/C offspring. These phenotypic changes were accompanied with suppressed hepatic lipogenic gene expression but enhanced expression of lipid oxidation-related genes. In the second experiment, we extended the earlier findings by examining whether adding BM to F-fed dams would still benefit offspring if they continued to consume the F diet postweaning. This simulates the scenario in affluent societies where fructose overconsumption may occur in two consecutive generations. The dose-response effect of BM at doses of 0.85% (FBM1) and 1% (FBM2) was also examined. Male offspring born to dams fed the C, F, FBM1 or FBM2 diet were weaned to C or F diet (C/C,C/F,F/F,FBM1/F,FBM2/F) for 20 weeks. BM normalized the serum FFA elevation observed in F/F offspring, although hyperinsulinemia remained in FBM1/F and FBM2/F offspring. The altered liver lipid profile and its molecular changes observed in F/F offspring were ameliorated by maternal BM supplementation. Lower adipose expression of mesoderm-specific transcript, hormone sensitive lipase, sterol regulatory element-binding transcription factor 1, and peroxisome proliferator-activated receptor-gamma (PPARγ) and PPARγ-target genes in FBM1/F and FBM2/F offspring indicated that BM could reduce adipocyte size as well as lower lipolysis and lipogenesis. Since FFA stimulates reactive oxygen species generation that enhances cellular stress, oxidative stress and inflammation in offspring of two-generation F exposure with or without maternal BM supplementation were examined. FBM1/F and FBM2/F offspring showed reduced lipid peroxidation but enhanced antioxidant capacity in the liver. BM suppressed the expression of proinflammatory genes and phosphorylation of c-Jun amino terminal kinase1, as well as promoted insulin receptor substrate 1 protein expression. These BM-mediated antioxidant and anti-inflammatory effects may be associated with a reduction of circulating FFA. Taken together, the data support the concept of developmental programming as maternal fructose clearly induced dyslipidemia, adipocyte dysfunction, oxidative stress and inflammation in offspring. That these abnormalities were largely reversed by adding BM to the maternal diet suggests that perinatal BFC supplementation could alter the course of maternal malnutrition-induced metabolic defects later in life. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Ovarian carcinoma is one of the most leading causes of cancer death among all gynaecologic malignancies worldwide. Although there are advances in cancer treatment for the last decades, the curative rate of this disease is just modestly improved. Chemoresistance is the major obstacle in clinical management of ovarian cancer nowadays. Thus, it is an urgent need for exploring effective alternative therapeutic strategies for ovarian cancer patients with advanced or recurrent disease. Emerging evidence has suggested that targeting cancer cell metabolism is the most promising molecular therapeutic approach in combating human cancers. Recently, the application of pharmaceutical AMPK activators is a plausible approach in selectively and specifically killing cancer cells without hampering normal cells. However, these pharmaceutical AMPK activators have many side-effects. Therefore, searching for replaceable reagents from nutraceuticals is a “new vista”. Bitter melon and its bioactive components are proposed to be natural activator of AMPK not only to reduce triglycerides levels in hyperlipidemic diabetic or insulin-resistant rodents but also to suppress human cancer cell growth specifically without toxicity to normal cells. In this study, the anti-cancer effect and molecular mechanism of bitter melon extract (BME) and one of its bioactive components, MAP30, on ovarian cancer cells were examined. Upon treatment of BME and MAP30, ovarian cancer cells showed a drastic reduction in cell proliferation and an increase of cell apoptosis in a dose dependent manner. Intriguingly, co-treatment of BME or MAP30 could enhance cisplatin-induced cell cytotoxicity in ovarian cancer cells. On the other hand, tumor microenvironement has been known as a key factor promoting cancer progression and chemoresistance. Results herein showed that BME or MAP30 could inhibit cell growth, cell migration and invasion of ovarian cancer cells mediated by omentum conditioned medium (OCM), as well as enhanced cisplatin-mediated cell cytotoxicity in a xenograft mouse tumour model. Mechanistic studies revealed that the inhibitory effect of BME and MAP30 was concomitantly associated with up-regulated AMPK activity but reduced expression of phospho-AKT, phospho-ERK and FOXM1. Such effects were similar to the functions of common AMPK activators e.g. AICAR, A23187, metformin or hypoxic stress, indicating that BME and MAP30 functions as natural AMPK activators in suppressing cancer cells growth through activating AMPK activity and inhibiting AKT/ERK/FOXM1 signaling cascade. Importantly, this study demonstrated that BME and MAP30 induced AMPK activation through an AMP-independent manner using a pair of isogenic HEK293 cells with overexpression of either the wild-type (WT) or R531G mutant isoform of AMPK2 subunit, implying the significance that BME and MAP30 may not affect the mitochondrial respiration and thus may be more tolerated by patients when used as anti-cancer medications. Taken together, the findings in this study suggest that the non-toxic BME and MAP30 function as natural AMPK activator in impairing ovarian cancer cell growth and enforcing cisplatin-mediated cell cytotoxicity in ovarian cancer cells through targeting cancer cell metabolism. Thus, BME or MAP30 may be used as a supplement for synergistically enhancing the efficacy of current chemotherapy regimes. / published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

published_or_final_version / Biological Sciences / Master / Master of Philosophy