published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / abstract / toc / Pharmacology / Master / Master of Philosophy

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Ganoderma lucidum is one of most popular medicinal mushrooms in oriental countries. The medicinal properties of Ganoderma lucidum in the treatment of various diseases have been documented for hundreds of years. In recent years, more and more attentions are paid on the studies of the action mechanisms of bioactive compounds purified from this mushroom. / In conclusion, the Ganoderma steroids EP and 9(11)-DHEP can induce caspase-dependent apoptosis in susceptible cancer cells via the mitochondria-mediated pathway. In vitro and in vivo studies suggested that these two fungal steroids have the potential to be used as natural chemopreventive agents. / Keywords: Ergosterol peroxide, 9(11)-dehydroergosterol peroxide, Ganoderma lucidum, Mycelia, Antitumor activity, Apoptosis / The antiproliferative activities of EP and 9(11)-DHEP were studied by flow cytometry. Exposure of cancer cells with these two fungal steroids resulted in an accumulation of cell population at the subG1 phase in a dosage- and time-dependent manner, indicating the induction of apoptotic cell death. Morphological apoptotic changes in HepG2 cells and A375 cells were observed using TUNEL assay and Annexin-V-FLUOS assay. The signaling pathway in apoptotic cell death induced by EP and 9(11)-DHEP involved the activation of caspase 3, 7 and 9, followed by the cleavage of PARP. In Colo201 cells, a change in the ratio of expression levels of Bcl-2/Bax was observed in cells treated with EP and 9(11)-DHEP. In A375 cells, exposure to EP and 9(11)-DHEP resulted in the release of mitochondrial cytochrome c, the down-regulation of Mcl-1 and a slight up-regulation of Bak in a dosage-dependent manner. All these results indicated that apoptotic cell death in susceptible cancer cells induced by EP and 9(11)-DHEP was via the mitochondria-mediated pathway. / The in vivo antitumor activity of EP was demonstrated. EP was shown to suppress the growth of A375 cells in a nude mice xenograft model. Further studies showed that EP induced the cleavage of PARP and enhanced the total caspase 7 gene expression in the tumor cells. / Triterpenes and steroids are two important classes of Ganoderma lucidum metabolites of low molecular mass that are responsible for the antitumor activities of the mushroom. In this study, two fungal steroids, namely, 5alpha,8alpha-epidioxy-22E-ergosta-6,22-dien-3beta-ol (ergosterol peroxide (EP)) and 5alpha,8alpha-epidioxy-22E-ergosta-6,9(11),22-trien-3beta-ol (9,11-dehydroergosterol peroxide (9(11)-DHEP)) were purified from the mycelia of Ganoderma lucidum grown under submerged culture using activity-guided purification procedures against human breast adenocarcinoma MCF-7 cells. In addition to MCF-7 cells, both of these two fungal steroids showed antiproliferative activities against other human cancer cells including hepatocellular carcinoma HepG2 cells, colorectal carcinoma Colo201 cells, esophageal squamous carcinoma KYSE cells and malignant melanoma A375 cells. However, EP and 9(11)-DHEP were less toxic to MCF-10-2A, non-tumorigenic human epithelial cells, and the normal human skin fibroblast Hs68 cells. / Zheng, Lin. / Adviser: Y. S. Wong. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0253. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 153-176). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

Ko, Wai Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 243-257). / Abstracts in English and Chinese. / Publications Based On The Work In This Thesis --- p.i / Abstract --- p.ii / Acknowledgements --- p.ix / Abbreviations --- p.x / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Prevalence of arthritis --- p.1 / Chapter 1.2 --- Pathogenesis of arthritis --- p.4 / Chapter 1.2.1 --- Histological changes --- p.6 / Chapter 1.2.1.1 --- Synovium changes --- p.6 / Chapter 1.2.1.2 --- Articular cartilage degradation --- p.8 / Chapter 1.2.1.3 --- Bone erosions --- p.10 / Chapter 1.3 --- Western medicines for arthritis --- p.14 / Chapter 1.3.1 --- Nonsteroidal anti-inflammatory drugs (NSAIDs) --- p.15 / Chapter 1.3.2 --- Glucocorticoids (GCs) --- p.18 / Chapter 1.3.3 --- Disease modifying antirheumatic drugs (DMARDs) --- p.20 / Chapter 1.3.4 --- Biological therapies --- p.22 / Chapter 1.4 --- Traditional Chinese medicines for arthritis --- p.24 / Chapter 1.4.1 --- Ganoderma lucidum (靈芝））) --- p.26 / Chapter 1.4.1.1 --- Major chemical constituents --- p.27 / Chapter 1.4.1.2 --- Functions --- p.27 / Chapter 1.4.2 --- Cortex Phellodendri (黃柏） --- p.28 / Chapter 1.4.2.1 --- Major chemical constituents --- p.29 / Chapter 1.4.2.2 --- Traditional description --- p.29 / Chapter 1.4.2.3 --- Functions --- p.30 / Chapter 1.4.3 --- Atractylodisa Rhizoma (蒼术) --- p.31 / Chapter 1.4.3.1 --- Major chemical constituents --- p.31 / Chapter 1.4.3.2 --- Traditional description --- p.32 / Chapter 1.4.3.3 --- Functions --- p.32 / Chapter 1.4.4 --- Radix Achyranthis Bidentatae (牛膝) --- p.33 / Chapter 1.4.4.1 --- Major chemical constituents --- p.34 / Chapter 1.4.4.2 --- Traditional description --- p.34 / Chapter 1.4.4.3 --- Functions --- p.34 / Chapter 1.5 --- Animal models of arthritis --- p.36 / Chapter 1.5.1 --- Adjuvant-induced arthritis --- p.37 / Chapter 1.6 --- Aims of study --- p.42 / Chapter Chapter 2 --- Materials and Drugs --- p.44 / Chapter Chapter 3 --- Methodology --- p.49 / Chapter 3.1 --- Induction of anaesthesia --- p.49 / Chapter 3.2 --- Induction of monoarthritis --- p.49 / Chapter 3.3 --- Measurements of knee extension angles --- p.50 / Chapter 3.4 --- Measurements of knee joint sizes --- p.51 / Chapter 3.5 --- Assessment of changes in articular blood flow --- p.52 / Chapter 3.6 --- Assessment of morphological changes --- p.53 / Chapter 3.6.1 --- Fixation --- p.53 / Chapter 3.6.2 --- Decalcification --- p.53 / Chapter 3.6.3 --- Processing --- p.54 / Chapter 3.6.4 --- Embedding --- p.54 / Chapter 3.6.5 --- Sectioning --- p.55 / Chapter 3.6.6 --- Staining --- p.55 / Chapter 3.6.7 --- Scoring --- p.56 / Chapter 3.7 --- Statistical analysis --- p.57 / Chapter Chapter 4 --- Adjuvant-induced Monoarthritic Rats / Chapter 4.1 --- Adjuvant-induced monoarthritic rats (1 week) --- p.58 / Chapter 4.1.1 --- Method --- p.58 / Chapter 4.1.2 --- Results --- p.59 / Chapter 4.1.2.1 --- Body weight --- p.59 / Chapter 4.1.2.2 --- Knee joint sizes --- p.59 / Chapter 4.1.2.3 --- Knee extension angles --- p.59 / Chapter 4.1.2.4 --- Knee joint blood flow --- p.60 / Chapter 4.1.2.5 --- Histological evaluation --- p.60 / Chapter 4.1.2.5.1 --- Cell infiltration --- p.60 / Chapter 4.1.2.5.2 --- Synovial tissue proliferation --- p.61 / Chapter 4.1.2.5.3 --- Cartilage degradation --- p.61 / Chapter 4.2 --- Adjuvant-induced monoarthritic rats (2 weeks) --- p.68 / Chapter 4.2.1 --- Method --- p.68 / Chapter 4.2.2 --- Results --- p.69 / Chapter 4.2.2.1 --- Body weight --- p.69 / Chapter 4.2.2.2 --- Knee joint sizes --- p.69 / Chapter 4.2.2.3 --- Knee extension angles --- p.69 / Chapter 4.2.2.4 --- Knee joint blood flow --- p.70 / Chapter 4.2.2.5 --- Histological evaluation --- p.70 / Chapter 4.2.2.5.1 --- Cell infiltration --- p.70 / Chapter 4.2.2.5.2 --- Synovial tissue proliferation --- p.71 / Chapter 4.2.2.5.3 --- Cartilage degradation --- p.71 / Chapter 4.3 --- Discussions --- p.78 / Chapter Chapter 5 --- Effects of intra-articular injection of LS in adjuvant-induced monoarthritic rats --- p.82 / Chapter 5.1 --- Method --- p.82 / Chapter 5.2 --- Results --- p.83 / Chapter 5.2.1 --- Body weight --- p.83 / Chapter 5.2.2 --- Knee joint sizes --- p.83 / Chapter 5.2.3 --- Knee extension angles --- p.85 / Chapter 5.2.4 --- Knee joint blood flow --- p.87 / Chapter 5.3 --- Discussions --- p.98 / Chapter Chapter 6 --- Effects of oral administration of LS in adjuvant-induced monoarthritic rats --- p.102 / Chapter 6.1 --- Oral administration of LS for 6 days after induction of arthritis --- p.102 / Chapter 6.1.1 --- Method --- p.102 / Chapter 6.1.2 --- Results --- p.103 / Chapter 6.1.2.1 --- Body weight --- p.103 / Chapter 6.1.2.2 --- Knee joint sizes --- p.103 / Chapter 6.1.2.3 --- Knee extension angles --- p.105 / Chapter 6.1.2.4 --- Knee joint blood flow --- p.106 / Chapter 6.1.2.5 --- Histological evaluation --- p.107 / Chapter 6.1.2.5.1 --- Cell infiltration --- p.107 / Chapter 6.1.2.5.2 --- Synovial tissue proliferation --- p.107 / Chapter 6.1.2.5.3 --- Cartilage degradation --- p.108 / Chapter 6.2 --- Oral administration of LS for 7 days before and 7 days after induction of arthritis --- p.131 / Chapter 6.2.1 --- Method --- p.131 / Chapter 6.2.2 --- Results --- p.132 / Chapter 6.2.2.1 --- Body weight --- p.132 / Chapter 6.2.2.2 --- Knee joint sizes --- p.132 / Chapter 6.2.2.3 --- Knee extension angles --- p.134 / Chapter 6.2.2.4 --- Knee joint blood flow --- p.137 / Chapter 6.2.2.5 --- Histological evaluation --- p.137 / Chapter 6.2.2.5.1 --- Cell infiltration --- p.137 / Chapter 6.2.2.5.2 --- Synovial tissue proliferation --- p.138 / Chapter 6.2.2.5.3 --- Cartilage degradation --- p.138 / Chapter 6.3 --- Oral administration of LS for 13 days after induction of arthritis --- p.165 / Chapter 6.3.1 --- Method --- p.165 / Chapter 6.3.2 --- Results --- p.166 / Chapter 6.3.2.1 --- Body weight --- p.166 / Chapter 6.3.2.2 --- Knee joint sizes --- p.166 / Chapter 6.3.2.3 --- Knee extension angles --- p.168 / Chapter 6.3.2.4 --- Knee joint blood flow --- p.169 / Chapter 6.3.2.5 --- Histological evaluation --- p.170 / Chapter 6.3.2.5.1 --- Cell infiltration --- p.170 / Chapter 6.3.2.5.2 --- Synovial tissue proliferation --- p.170 / Chapter 6.3.2.5.3 --- Cartilage degradation --- p.171 / Chapter 6.4 --- Discussions --- p.194 / Chapter Chapter 7 --- Effects of intra-peritoneal administration of LS in adjuvant-induced monoarthritic rats --- p.203 / Chapter 7.1 --- Method --- p.203 / Chapter 7.2 --- Results --- p.204 / Chapter 7.2.1 --- Body weight --- p.204 / Chapter 7.2.2 --- Knee joint sizes --- p.205 / Chapter 7.2.3 --- Knee extension angles --- p.207 / Chapter 7.2.4 --- Knee joint blood flow --- p.209 / Chapter 7.2.5 --- Histological evaulation --- p.209 / Chapter 7.2.5.1 --- Cell infiltration --- p.209 / Chapter 7.2.5.2 --- Synovial tissue proliferation --- p.210 / Chapter 7.2.5.3 --- Cartilage degradation --- p.210 / Chapter 7.3 --- Discussions --- p.237 / Chapter Chapter 8 --- Conclusions --- p.239 / References --- p.243