Thesis (M. Phil.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 105-117).

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published_or_final_version / Botany / Master / Master of Philosophy

Curcumin is one of the major curcuminoids produced by the ginger family Zingiberaceae. These curcuminoids possess pharmacological properties that include anticancer activities. We have evaluated some synthetic curcumin analogues that have shown potential as anticancer drugs. These antineoplastic agents bearing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore are electrophiles which are designed to preferentially react with sulfhydryl groups present in proteins as opposed to amino and hydroxyl groups present in DNA. In previous pilot studies, three derivatives examined in this thesis showed inhibition towards human cancer cell lines such as Molt 4/C8 and CEM T-lymphocytes. In this thesis work, I determined the cytotoxicity of these derivatives and curcumin towards human colon cancer (HCT-116) cells and also normal colon epithelial (CRL-1790) cells, and examined the possible mechanism(s) involved. I hypothesized that they act via induction of reactive oxygen species (ROS) which elicit a transient surge of mitochondrial ROS generation and a phenomenon known as ROS-induced ROS release (RIRR), along with the mitochondrial permeability transition (MPT) and mitochondrion –dependent apoptosis. I asked whether these agents react with some of the key protein thiols in the mitochondria whose oxidation/alkylation results in mitochondrion - dependent apoptosis. NC-2109 and NC-2346 were found to be potent cytotoxic agents based on their GI50 values of 0.87 ± 0.38 μM and 0.90 ± 0.22 μM, respectively, and were more potent than the anticancer drug 5-fluorouracil (GI50 = 5.47 ± 0.55 μM) and curcumin (GI50 = 3.50 ± 0.36 μM). However NC-2109 was found to have a better selectivity towards cancer cells over normal cells (a selectivity index of 18.81 versus 5-FU, curcumin and NC-2346 which had selectivity indices of 1.87, 16.75 and 4.61, respectively). In the investigations of the mechanisms involved, both curcumin and curcumin analogues were able to induce mitochondrial ROS production. Moreover, curcumin and its synthetic counterparts showed a biphasic ROS profile which is most characteristic of RIRR. Treatment with these agents also led to the disruption of the mitochondrial membrane potential, suggesting oxidation of protein thiols and the opening of the mitochondrial permeability transition pore which is an important step to initiate mitochondria-directed apoptosis. This possibility was confirmed based on GSSG/GSH ratios, since curcumin, NC-2346 and NC-2109 all produced a higher GSSG/GSH ratio than the controls. In addition to their ability to depolarize the mitochondrial membrane in HCT-116 cells, that these molecules acted via the mitochondrial pathway were further authenticated based on their ability to induce mitochondrial swelling in rat liver mitochondria. In another part of this thesis I evaluated the involvement of the critical thiol protein adenine nucleotide translocase (ANT), a bifunctional protein that plays a central role in mitochondrial apoptosis. ANT has four different isoforms; ANT1 and ANT3 are proapoptotic, while ANT2 and ANT4 are antiapoptotic and are overexpressed in cancer states. A combination approach using ANT2 siRNA however did not conclusively show whether these agents acted synergistically with ANT2 knockdown to potentiate mitochondria-mediated cell death. An alternative combination approach was the use of carboxyatractyloside (CAT) which binds to and retains ANT in its ‘c’ conformation, exposing thiols and potentially driving a cell towards programmed cell death. The presence of CAT enhanced the ability of curcumin and its synthetic analogs to collapse the mitochondrial membrane potential, an important step in mitochondrial-mediated apoptosis. In conclusion, curcumin and the curcumin analogue NC-2109 were found to be cytotoxic in vitro, towards HCT-116 cells and also showed good selectivity. In addition, these two molecules were found to be ROS inducers, and coincidentally oxidized cellular thiols and caused depolarization of the mitochondrial membrane potential. The results support a mechanism of mitochondrial-mediated cell death upon MPT pore formation (mitochondrial swelling), perhaps involving ANT2. This conclusion was further supported by the potentiation of cell death in the presence of the ANT2 inhibitor, CAT.

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The design of pile foundations in conventional geotechnical engineering practice is based on the soil mechanics principles for saturated soils. These approaches are also extended to pile foundations that are placed totally or partially above the ground water table (i.e., vadose zone), where the soil is typically in a state of unsaturated condition. Such approaches lead to unrealistic estimations of the load carrying capacity and the settlement behavior of pile foundations. Some studies were undertaken in recent years to understand the influence of the matric suction towards the bearing capacity of model pile foundations placed in unsaturated fine-grained and coarse-grained soils. The conventional   and methods were modified to interpret the contribution of shaft carrying capacity of single piles in fine-grained soils (e.g., Vanapalli and Taylan 2011, Vanapalli and Taylan 2012). Also, the conventional method has been used to understand the contribution of matric suction towards the shaft resistance in unsaturated sands (Vanapalli et al. 2010). One of the key objectives of the present research study is directed to determine the contribution of matric suction towards the bearing capacity and settlement behavior of model single pile foundations in unsaturated sands. A series of single model pile load tests were performed in a laboratory environment to study the contribution of the matric suction towards the total, shaft, and base bearing capacity of the model piles with three different diameters (i.e., 38.30, 31.75, and 19.25 mm) in two unsaturated sands (i.e., a clean commercial sand and a super fine sand). Hanging column method (i.e., plexi glass water container) was used to control the matric suction values in the compacted sands in the test tank by varying the water table. The results of the testing programs indicate the significant contribution of the matric suction towards the bearing capacity of single model piles (i.e., 2 to 2.5 times of base bearing capacity and 5 times of shaft bearing capacity under unsaturated conditions in comparison with saturated condition). The test results were interpreted successfully by modifying the conventional methods for estimating the pile shaft bearing capacity (i.e., β method) and base bearing capacity (i.e., Terzaghi 1943, Hansen 1970 and Janbu 1976). In addition, semi-empirical methods were proposed for predicting the bearing capacity of single model piles using the effective shear strength parameters (i.e., c' and ϕ') and the soil-water characteristic curve (SWCC). There is a good agreement between the measured and the predicted bearing capacity of single model piles using the semi-empirical models proposed in this study. In addition, numerical investigations were undertaken using the commercial finite element analysis program SIGMA/W (Geostudio 2007) to simulate the load-displacement (i.e., p-δ) behavior of the single model piles for the two sands (i.e., clean commercial sand and super fine sand) under saturated and unsaturated conditions. An elastic-perfectly plastic Mohr-Coulomb model that takes into account the influence of the matric suction was used to simulate the load-displacement (i.e., p-δ) behavior. The numerical approach proposed in this thesis is simple and only requires the information of the effective shear strength parameters (i.e., c' and ϕ'), the elastic modulus (i.e., Esat) under saturated conditions, the soil-water characteristic curve (SWCC), and the distribution of the matric suction with respect to depth. The approaches proposed in this thesis can be extended to determine the in-situ load carrying capacity of single piles and also simulate the load-displacement (i.e., p-δ) behavior. The studies presented in this thesis are promising and encouraging to study their validity in-situ conditions. Such studies will be valuable to implement the mechanics of unsaturated soils into geotechnical engineering practice.

Levees are earth structures used for flood protection. Due to their easy availability and low permeability, clays are the most common material used for the construction of levees. Clays are susceptible to desiccation cracks when subjected to long dry spells during summers. There has been an increased interest in studying the occurrence of cracks in soil mass. In particular, many experimental investigations for soils have been undertaken to learn about the crack pattern in earth embankment. However, there is a dearth of work that focuses on the numerical modeling of desiccation cracks effects on levees. This study has been undertaken to analyze the effect of desiccation cracking on the hydraulic behavior of an earth embankment under flooding conditions. A numerical model was developed using the finite element package CODE_BRIGHT. The model was validated from the data obtained from a small scale embankment experiment under controlled environmental conditions. As the phenomenon of desiccation cracking is highly random, a simple random model was developed to capture the variability in crack geometry. The random crack geometry was then passed on to the finite element mesh, so that a probabilistic analysis can be carried out using a Monte Carlo approach, for assessing the embankment’s integrity. The results obtained from the analysis such as time to steady state saturation and steady state flow rate at the outward slope were very interesting to study and provided an insight on the effect of desiccation cracks on unsaturated earth embankments.

Bibliography: leaves 242-298. / xxxiii, 298 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis investigates the effects of polyunsaturated fatty acids (PUFAs) on macrophage oxygen radical production. The role of fatty acid structure in the ability to stimulate the fMLP response is also examined. The mechanisms by which fatty acids induce their effects on mononuclear phagocytes are partially elucidated. The mechanisms of the biological effects of the PUFAs in terms of intracellular signalling pathway are partly defined. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 1997

Bibliography: leaves 242-298. / xxxiii, 298 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis investigates the effects of polyunsaturated fatty acids (PUFAs) on macrophage oxygen radical production. The role of fatty acid structure in the ability to stimulate the fMLP response is also examined. The mechanisms by which fatty acids induce their effects on mononuclear phagocytes are partially elucidated. The mechanisms of the biological effects of the PUFAs in terms of intracellular signalling pathway are partly defined. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 1997