Hepatocellular carcinoma (HCC) is the primary cancer of liver. It is the fifth common malignant tumor in men while seventh common in women. Aetiology of HCC is complex; however, it is now believed that sustained chronic liver injury and fibrosis are critically involved in the development of HCC. Prevention and treatment of HCC is far from desirable and prognosis remains poor. Coptis is a Chinese herbal Medicine which has been used for more than thousands years for clearing heats, dampness and toxics. Recently, studies from our group reported the hepatoprotective effect of Coptis and its major active component, berberine, on acute liver injury and berberine was extensively studied for their anti-tumor effect. However, there’s no comprehensive investigation focusing on the preventive and curative potential of berberine on HCC. Hence, here we hypothesized Coptis and berberine exhibits both preventive and curative effects on HCC. The prevention of HCC by berberine and Coptis may rely on their effects on chronic liver damage and fibrosis, and the curative action may depend on their actions on the angiogenesis, tumor growth and invasion of HCC. Both in vitro cell models and in vivo animal system were used in our study and some molecular events were investigated. We found that berberine and Coptis could significantly attenuate the chronic liver injury and fibrosis by restoring the anti-oxidative enzyme SOD activity in CCl4-, bile duct ligation- and alcohol-induced liver injury and fibrosis model. Recovery of SOD activity prevents the hepatocytes from apoptosis by inhibiting the oxidative stress-induced Erk1/2 signaling activation. The prevention of berberine and Coptis on chronic liver injury and fibrosis may contribute to its preventive effect against HCC. Then we found that berberine (as representative to Coptis) could suppress the angiogenesis of HCC, in which berberine does not directly act on the blood vessel formation, but suppress the expression and secretion of pro-angiogenic factors VEGF in HCC cells, and Id-1 inhibition by berberine plays a central role in the suppression of HIF-1α/VEGF and NF-κB pathways. We also found that berberine could induce both apoptotic and autophagic cell death in HCC, and the mitochondria related-caspases activation confers the apoptosis while mTOR inhibition initiates autophagy in berberine treated- cells. We found that berberine could suppress the migration and invasion of HCC cells as well, and Rho-GTPases/ROCK signaling is the particular target in berberine’s anti-invasive action. Finally, to dig out some molecular events involved in berberine’s action on HCC, we studied critically the mechanism underlying berberine’s inhibition on Cyclin D1 in HCC. We found berberine may promote the IKKα-induced Cyclin D1 phosphorylation at T286, and this may initiate the ubiquitination-dependent proteasomal degradation of Cyclin D1 in berberine-treated HCC cells and contribute to berberine’s anti-HCC action. Critical clinical trials and OMICS techniques were planned to further our comprehensive study on Coptis and berberine’s effects on HCC. In all, we found that berberine targets on different stages and molecules and exerts preventive and curative potential against HCC. Our study sheds light on the clinical application of berberine in HCC treatment. / published_or_final_version / Chinese Medicine / Doctoral / Doctor of Philosophy

Background: A study of the impact of yoga and aerobic exercise and psychosis was conducted in 2012 by Lin et al., from The University of Hong Kong. The study indicated significant improvement in the aspects of physical fitness, cognitive functions, psychosocial and emotional functioning in patients with psychosis after a 12-week yoga or aerobic intervention program. Long-term effect of exercise intervention, however, had yet been determined. The aim of the present study was to evaluate the long-term effects of yoga and aerobic exercise on cognitive functioning and clinical symptoms in early psychosis. Patients who originally participated in Lin et al.’s 2012 study were recruited and re-assessed in this current 18-month follow-up study. Methods: Two intervention groups (yoga and aerobic exercise group) and one control group (wait-list control group) of a total 57 subjects from the initial study were recruited in this follow-up study. Cognitive functioning and clinical symptoms were assessed at three time points (T1:Baseline, T2:12-week, T3:18-month). Results: No significant changes or significant deterioration were found in cognitive functioning, clinical symptoms and depression between T2 (12-week) and T3 (18-month) in both intervention groups (yoga and aerobic group). Significant improvement of clinical symptoms was observed in wait-list control group at T3. Conclusions: Although there is no significant finding in this current study, it is still recommended that further study on the relationship between physical exercise intervention and psychosis should carried out in order to explore other adjunct, and especially low cost, treatment to antipsychotics in treating people with psychosis. / published_or_final_version / Psychological Medicine / Master / Master of Psychological Medicine

Prompted by the successful clinical application of cisplatin in cancer therapy, worldwide efforts have been devoted to develop new metal-based drugs for anticancer treatment. Gold(III) complexes at first received attention as anti-cancer drug candidates because of their square-planar geometry which resembles that of platinum(II) complexes. Subsequent studies revealed that various gold(III) complexes displayed promising anti-cancer activities with different biological mechanisms. Although some achievements have been obtained in the development of anti-cancer gold(III) complexes, challenges including the improvement of bioavailability, stability and selectivity, elucidation of the action mechanisms, and the development of novel delivery approaches of gold(III) complexes to reduce systematic toxicity, remain to be exploited. A panel of anti-cancer complexes [AuIII(R-C^N)(L)]n+ (wherein HC^N is 2-phenylpyridine, L is biguanide or biuret) have been identified and described in Chapter 3. Biguanide or biuret have been employed to improve the solubility of the complexes in aqueous solutions. Meanwhile, the lipophilicity could readily be adjusted by varying the R group to obtain a balance between lipophilicity and aqueous solubility. Among the synthesized complexes, the cationic complexes, [AuIII(butyl-C^N)biguanide]Cl (3.1) and [AuIII(C^N)biguanide]Cl (3.2) are soluble in aqueous solutions with solubility over 5 mg/mL. Besides, introduction of butyl groups to 3.1 and [AuIII(butyl-C^N)biuret] (3.3) resulted in higher cellular uptake of gold, which might enhance their cytotoxic activities (IC50 values: 1.5–17 μM) compared with 3.2 and [AuIII(C^N)biuret] (3.4) (IC50 values: 9.4–47.3 μM). Moreover, 3.1 was also found to induce cell cycle arrest in S-phase and endoplasmic reticulum (ER) damage in human cervical epithelial carcinoma (HeLa) cells, and display significant anti-angiogenic activity at its sub-cytotoxic concentrations. In Chapter 4, a series of gold(III) complexes with dithiocarbamate and 2-phenylpyridine ligands to target deubiquitinases (DUBs), have been designed. These complexes achieved significant inhibition on purified DUBs. Notably, [AuIII(2-(4-nbutylphenyl) pyridyl)(diethyldithiocarbamate)]PF6 (4.1) inhibited both the purified (IC50 values: 46–223 nM) and cell-based DUBs activities with high efficiency. Its interaction with DUB UCHL1 and peptides which are present in several types of DUBs and contain active cysteine residue were confirmed by mass spectrometric analysis. All complexes displayed significant cytotoxicities, and those containing diethyldithiocarbamate ligand displayed specific cytotoxicity on breast cancer cells. Accumulation of a tumor suppressor p53, cell-cycle arrest, and apoptotic cell death were induced in breast cancer cells by 4.1. Besides, 4.1 also showed anti-angiogenic effects. These biological activities might be related with DUBs inhibition. In Chapter 5, a cytotoxic complex [AuIII(C^N^C)(4-dpt)](CF3SO3) (5.1, HC^N^CH = 2,6-diphenylpyridine; 4-dpt = 2,4-diamino-6-(4-pyridyl)-1,3,5-triazine) has been designed to self-assemble into supramolecular polymers (5.1-SP) in acetonitrile. In physiologically relevant solutions, 5.1-SP displayed a sustained-release property of the anti-angiogenic ligand 4-dpt, and in the presence of glutathione (GSH), [AuIII(C^N^C)-GSH] adduct(s) were also gradually released. The supramolecular polymers 5.1-SP also showed selective cytotoxicity toward cancerous cells, and could act as drug-carriers of other cytotoxic agents to achieve sustained-release behavior. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

In a 6-week rat model it was demonstrated that a small dose of peri-implant zoledronic acid (ZA) increased local bone formation 3-fold compared with controls. Ancillary in vitro studies using 14C-labeled ZA implant doses demonstrated biphasic elution profiles for implants coated with hydroxyapatite; complete ZA release occurred within one to three weeks in serum compared with only 60% ZA release after 12 weeks in water. Implants without hydroxyapatite coating showed more burst-type release profiles and full ZA elution within 24 hours of hydration in serum or water. Canine studies at 6 weeks using implants with 14C-labeled ZA showed that the compound remained localized, with the greatest ZA concentration immediately adjacent to the implant. Although there was evidence of skeletal ZA distribution via diffusion into the circulation, the levels were two orders of magnitude less than at the implant site.

This thesis is a step forward in evaluating insulin therapy and defining its role in cardiac surgery first described as Glucose-Insulin-Potassium (GIK) solution 40 years ago. / Chapter (I) includes a review of the literature on insulin therapy in cardiac surgery and illustrates the scientific bases and controversies in this therapy. / Chapter (II) entitled: "Myocardial Protection During Elective Coronary Artery Bypass Grafting Using High Dose Insulin Therapy" represents a manuscript that was presented in the following meetings: (A) Local meetings: (1) McGill cardiovascular research day, February 1/2007, Montreal, Canada. (2) Fraser Gurd annual research day, McGill surgery department, May 31/2007, Montreal, Canada. (B) National meetings: (1) 11th Annual Terrence Donnelly research day for Canadian cardiac surgery residents, May 26/2007, Toronto, Canada. (C) International meetings: (1) 43rd Annual meeting of the Society of thoracic surgeons (STS), January 30/2007, San Diego, United States. A full manuscript was submitted to "The Annals of Thoracic Surgery" for review. / Chapter (III) entitled: "High Dose Insulin Therapy Attenuates Systemic Inflammatory Response in Patients Undergoing Elective Coronary Artery Bypass Grafting" represents a manuscript that was presented in the following meetings: (A) Local meetings: (1) Fraser Guard McGill Surgery department annual research day, May 3/2006, Montreal, Canada. (B) National meetings: (1) 10th Annual Terrence Donnelly research day for Canadian cardiac surgery residents, May 26/2007, Toronto, Canada. (2) Young investigator forum, Canadian Society of Clinical Investigators (CSCI), September 28/2006, Ottawa, Canada. (3) 59 th annual meeting of Canadian Cardiovascular Society (CCS), October 21/2006, Vancouver, Canada. (C) International meetings: (1) American Heart Association (AHA), November 12/2006, Chicago, United states. / Abstracts from this work were published in the following journals: (1) Clinical and Investigative Medicine, Vol. 29, No. 4, August 2006. (2) The Canadian Journal of Cardiology, Vol. 22 supp D, October 2006 (3) Circulation, Vol. 114 supp, No. 18, October 2006. / A full manuscript was submitted to "the journal of thoracic and cardiovascular surgery" for review.

The high performance of bone implants depends on the positive response of osteoblasts to the surface of the materials manufactured for the implant. Cell response in turn strongly depends on the nature of the initial interaction of macromolecules involved in cell adhesion and proliferation with the atomic structure of the surface of the material used for the implant. The initial interaction between bone specific extracellular matrix proteins and the solid substrate influences cell response at the cell-implant interface. This interaction is crucial for implant stability, long-term durability, and osseointegration. Despite extensive research undertaken to develop high-quality material for implants in order to improve the cell-substrate interaction, little is known about the significance of the atomic structure of the substrate and the role of molecular machinery involved in cell-substrate interaction. Using a combined approach involving material sciences and cell and molecular biology, the objectives of this research are to evaluate the response of pre-osteoblast and fibroblast cell lines to novel bulk polycrystalline and single crystal titanium based material and assess the role of crystal size and orientation. / Novel bulk nano-structured titanium substrates were produced by the process of high-pressure torsion (HPT). These materials have a significant advantage compared to conventional titanium-based materials by having higher surface wettablity, mechanical properties as well as a distinct surface oxide layer and atomic structure. A co-culture system was adapted to investigate the differential response of pre-osteoblast and fibroblast cell lines to titanium and titanium dioxide single-crystal substrates. / The results of this study provide clear evidence that crystal size and specific crystallographic orientation can be used to improve cell adhesion and proliferation. The nanostructured titanium substrates show strong interaction with pre-osteoblast cells as evident by the higher expression of fibronectin and the formation of extensive focal adhesion. Differential cell behaviour of pre-osteoblasts and fibroblasts are observed in cultures grown on the substrates with specific crystallographic orientations. The degree of cell attachment of the pre-osteoblasts is considerably higher on Ti-(1120) crystal face compared with the fibroblasts. These findings have profound implications for the improved osseointegration and inhibition of fibrosis leading to long-term implant consolidation and stability.