Opposite angiogenic outcome of curcumin against ischemia and Lewis lung cancer models: in silico, in vitro and in vivo studies

AbstractThe aim of this study was to investigate the angiogenic effects of curcumin on an ischemia and lung cancer model. To induce ischemia combined with lung cancer models, unilateral femoral arteries of C57BL/6 mice were disconnected on one side of the mouse and Lewis lung carcinoma (LLC) cells were xenografted on the opposite side. Angiogenic effects and underlying mechanisms associated with curcumin were investigated. Molecular target(s), signaling cascades and binding affinities were detected by Western blot, two-dimensional gel electrophoresis (2-DE), computer simulations and surface plasmon resonance (SPR) techniques. Curcumin promoted post-ischemic blood recirculation and suppressed lung cancer progression in inbred C57BL/6 mice via regulation of the HIF1α/mTOR/VEGF/VEGFR cascade oppositely. Inflammatory stimulation induced by neutrophil elastase (NE) promoted angiogenesis in lung cancer tissues, but these changes were reversed by curcumin through directly reducing NE secretion and stimulating α1-antitrypsin (α1-AT) and insulin receptor substrate-1 (IRS-1) production. Meanwhile, curcumin dose-dependently influenced endothelial cells (EC) tube formation and chicken embryo chorioallantoic membrane (CAM) neovascularization. Curcumin had opposite effects on blood vessel regeneration under physiological and pathological angiogenesis, which was effected through negative or positive regulation of the HIF1α/mTOR/VEGF/VEGFR cascade. Curcumin had the promise as a new treatment modality for both ischemic conditions and lung cancer simultaneously in the clinic

Dyslipidemia

Dyslipidemia has a complex pathophysiology consisting of various genetic, lifestyle, and environmental factors. It has many adverse health impacts, notably in the development of chronic non-communicable diseases. Significant ethnic differences exist due to the prevalence and types of lipid disorders. While elevated serum total- and LDL-cholesterol are the main concern in Western populations, in other countries hypertriglyceridemia and low HDL-cholesterol are more prevalent. The latter types of lipid disorders are considered as components of the metabolic syndrome. The escalating trend of obesity, as well as changes in lifestyle and environmental factors will make dyslipidemia a global medical and public health threat, not only for adults but for the pediatric age group as well. Several experimental and clinical studies are still being conducted regarding the underlying mechanisms and treatment of dyslipidemia. The current book is providing a general overview of dyslipidemia from diverse aspects of pathophysiology, ethnic differences, prevention, health hazards, and treatment

Effect of polyphenols on glucoregulatory biomarkers, blood pressure and lipid profile in overweight and obese subjects

This thesis describes a series of in vitro, animal and humans studies conducted with the aim of investigating the effect of polyphenol-rich green coffee bean extract (GCBE) and dark chocolate (DC) on biomarkers of glucose metabolism, lipid profile and blood pressure (BP) in overweight and obese individuals. Green coffee and Theobroma cacao bean extracts were found to be rich in polyphenols and to act as effective free radical scavenging compounds in vitro. A potential role for GCBE in inhibiting pancreatic lipase was identified in vitro. Preliminary human studies revealed a differential effect of GCBE and DC on fasting glucose, total cholesterol, BP and urinary glucocorticoids. Accordingly, consumption of 200mg GCBE containing 90mg chlorogenic acid (CGA) twice daily for 14 days by healthy overweight and obese volunteers reduced systolic BP (P=0.043), urinary free cortisone (P=0.0015) and waist circumference (-0.78cm; P=0.013) but raised salivary cortisone (P=0.042) without significantly affecting capillary fasting glucose, total cholesterol or urinary antioxidant excretion (P>0.05). The ability of CGA to differentially regulate cortisol metabolism was further highlighted in male C57BL6 mice wherein daily administration of a diet containing 0.15% CGA for 17 days marginally increased cortisol in kidney (P=0.108; eta2=0.26) and reduced hepatic cortisol (P=0.219; eta2=0.14). In the preliminary single-blind randomised cross-over DC study, 2-week consumption of 20g DC containing 500mg or 1000mg polyphenols by overweight and obese individuals produced equal reductions in capillary fasting glucose, systolic and diastolic BP. This was further confirmed by the long-term placebo-controlled trial wherein ingestion of 20g DC (500mg polyphenols) for 4 weeks reduced fasting glucose (P=0.028), insulin resistance (P=0.005), systolic (P=0.020), diastolic BP (P=0.008) and improved insulin sensitivity (QUICKI, P=0.04; revised-QUICKI, P=0.026) and urinary antioxidant capacity (total phenolics, P=0.046; ferric-reducing capacity, P=0.048) without significantly affecting lipid profile (P>0.05). A particular contribution of the main study is the finding that overweight and obese individuals respond more effectively to polyphenol-rich DC, compared to lean individuals, but more adversely to polyphenol-deficient placebo. The latter was marked by the rise in fasting insulin, insulin resistance and salivary cortisol. In conclusion, this thesis supports a role for polyphenol-rich GCBE and DC in counteracting overweight and obesity-related complications. The role of GCBE and CGA in modulating glucocorticoid metabolism emerges as a novel and potentially relevant field of research to the prevention of overweight and obesity-related complications.EThOS - Electronic Theses Online ServiceGBUnited Kingdo