Background Dementia is a leading cause of disability and dependency in elderly people, generating significant physical, psychological, and financial challenges for patients, caregivers, and healthcare systems worldwide. For Alzheimer’s disease (AD), the most common form of dementia, established treatments such as Acetyl-Cholinesterase Inhibitors (AChE) have proven to be marginally beneficial, but side effects remain. Alternatively, a standardized preparation of Ginkgo Biloba Extract (EGb-761) is a popular herbal medicine used globally and widely available in Hong Kong. This paper reviews and synthesizes the effectiveness of EGb-761 in the treatment of AD compared to placebo and AChE treatments. Methods A systematic search was performed using PubMed, ProQuest, and Google Scholar to identify all relevant randomized controlled studies in English that examined the effectiveness of EGb-761 on individuals with AD. The studies, based on expert consensus, had to have a minimum duration of 22 weeks and one of two primary outcome measures: 1. cognitive functioning, 2. functional ability in activities-of-daily-living (ADL). A secondary outcome measure, safety (drop-out rate from adverse events), was also evaluated. Quality was assessed based on indicators derived from the CONSORT 2010 checklist. Findings Ten randomized controlled trials from eight countries, with participants ranging from mild to severe AD were included. Of the ten studies, eight compared EGb-761 with placebo, three compared EGb-761 head-to-head with an AChE (two with Donepezil, one with Rivastigmine), and one compared EGb-761 and AChE stand-alone treatment with combined treatments (EGb-761 + AChE). Overall results on cognitive and functional improvements were mixed. Of the studies that demonstrated a positive association, the clinical significance is questionable. Conclusions Although results were inconsistent, EGb-761’s safety appears to be acceptable. In Hong Kong, given the widespread availability, popularity and perceived safety of EGb-761, the population needs appropriate guidance and support from the government to safeguard quality and increase awareness of potential drug-herb interactions. Concurrently, with AChE becoming an increasingly established treatment for AD, more head-to-head studies on EGb-761 and AChE on the local population are needed to increase understanding and public awareness. / published_or_final_version / Public Health / Master / Master of Public Health

Matrix metalloproteinase (MMP) induced extra cellular matrix (ECM) degradation is a crucial process involved in the development of many chronic inflammatory diseases, including cardiac remodeling and cancer metastasis. In cardiac remodeling, the presence of pathological stimuli leads to elevated MMP-9 expression and impairment of cardiac performance, which subsequently develops into heart failure. While in tumorgenesis, MMP-9 has been found to play key roles in metastasis, as it can break physical barriers for the tumor. Therefore, searching for agents targeting MMP-9 is a new direction for the treatment of cardiac remodeling and cancer metastasis. Chinese herbal medicine is becoming increasingly used worldwide in recent decades. In the past twenty years, as many highly selective and sensitive bioassays were introduced into the bioactive compounds screening from herbal medicine, more than one hundred new drug candidates have been identified. Therefore, herbal medicine is a potential source of bioactive compounds. Panax notoginseng (PNG) is one of the most common traditional Chinese medicines to treat cardiovascular diseases, and it was also reported to have anti-cancer effect. We hypothesized that it contains bioactive compounds that could inhibit MMP-9 activity in cardiomyocytes and cancer cells. In order to examine the effect of PNG on cardiac remodeling and cancer metastasis, we employed TNF-α induced MMP-9 in H9c2 cell (a rat cardiomyocyte) and HepG-2 cell (a human hepatoma cell) as an in vitro assay, respectively. PNG was first extracted by four different extraction methods according to the polarity of the solvent. The most effective fraction in suppressing MMP-9 activity in TNF-α induced H9c2 cell was chosen for further separation by silica gel column chromatography and high performance liquid chromatography (HPLC) until a single compound was isolated. According to the result of spectroscopic analysis by NMR, the compound was identified as ginsenoside Rb1. For the bioactivity assays, real-time quantitative polymerase chain reaction (QPCR) and Enzyme-linked immunosorbent assay (ELISA) were used to measure the mRNA and protein expression of MMP-9, respectively. We also examined the MMP-9 activity by gelatin zymography. The results showed that both of the PNG extract obtained from 10% ethanol extraction method (PNG-3) and purified Compound P (ginsenoside Rb1) showed significant inhibitory effect on MMP-9 expression and activity in H9c2 cells and HepG-2 cells. We further examined the molecular mechanisms of the inhibitory effect of PNG-3. H9c2 and HepG-2 cells were pretreated with different kinase inhibitors followed by the activation by TNF-α. The results showed the protein kinase R (PKR) inhibitor could inhibit TNF-α induced MMP-9 in both of the two cell lines. Furthermore, the results of Western blot showed the PNG-3 suppressed the phosphorylation of eIF-2α which is a down-stream effector of PKR in TNF-α stimulated H9c2 and HepG-2 cells, respectively. Therefore, PNG-3 may act through PKR to regulate TNF-α induced MMP-9 activity. In summary, bioactivity guided fractionation is an effective way of isolating bioactive compounds from medicinal herbs. In addition, PNG containing ginsenoside Rb1 may be a potential candidate of MMP-9 inhibition for the treatment of cardiac remodeling and cancer metastasis. / published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

Skeletal system plays a crucial role in our life. Skeletal diseases and disorders unlike cancer, are not fatal, but affect the quality of our life. Cell-based therapeutic strategies to generate targeted desired cell types for repair or replacement of damaged skeletal tissues are ideal regenerative medicines. Because of the heterogeneous cell types generated from embryonic and mesenchymal stem cells, the ability of progenitor population to differentiate into a target cell type appear to be a better alternative for tissue regeneration. Osteo-chondroprogenitors uniquely co-expressing Sox9 and Runx2 with dual differentiation potential to become chondrocytes and osteoblasts is a progenitor cell which is suitable for cell based therapy of bone disease. Therefore, developing effective strategies to generate sufficient quantities of osteo-chondroprogenitors are essential. Toward this, we took advantage of two lineage conversion approaches. The first strategy was to interrogate the ability of osteoblasts to be reprogrammed into induced pluripotent stem (iPS) cells and another one was to use defined transcription factors to induce chondrocyte lineage from skin fibroblasts. The selection of osteoblasts is based on the fact that it is originally derived from osteo-chondroprogenitor lineage and the stochastic events of iPS induction might revert osteoblasts first to their progenitor state before becoming pluripotent. The second approach is based on a previous report using three transcription factors (Sox9, Klf4 and c-Myc) to reprogramme skin fibroblasts into chondrocyte lineage. Our aim is to examine whether osteo-chondroprogenitors would be formed during the two reprogramming processes using Sox9-EGFP knock-in mice as a reporter. We reasoned that osteoblasts can be reprogrammed into iPS cells by four Yamanaka’s factors with pluripotency as shown by their ability to form teratomas and contribute to chimeric embryos. However base on the limitation of selector marker of osteo-chondroprogenitor we still cannot capture this progenitor during iPS reprogramming. And because of the pluripotency potential, pluripotent reprogramming approach also brings high risk of teratoma formation. Therefore our second objective was performed to examine whether osteo-chondroprogenitors would be formed during lineage reprogramming. Transient appearance of Sox9-EGFP/Runx2+ve cells was observed in the intermediate stage of over 14 days of chondrocyte lineage induction from skin fibroblasts by Sox9, klf4 and c-Myc. Cells expressing Sox9-EGFP/Runx2+ve showed typical molecular markers of osteo-chondroprogenitors. In vitro and in vivo differentiation assays demonstrated that Sox9-EGFP/Runx2+ve cells can differentiate predominantly into osteoblasts and chondrocytes. Taken together our data indicate that cells with osteo-chondrogenic potential could be generated by defined transcription factors-mediated reprogramming processes. / published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

Chronic heart failure is one of the commonest fatal diseases in the world. Much work has been done to reveal its complicated pathogenesis and develop effective therapy. Xinmailong (XML), a compound extracted from Periplaneta americana, has been launched on the market in Mainland China as a proprietary medication for treating patients with chronic heart failure. Although it is highly effective, its mechanism of action is still not completely understood. In this study, the results of calcium (〖Ca〗^(2+)) imaging demonstrated that XML increased electrical impulse-induced intracellular calcium ([〖Ca〗^(2+)]i), in H9c2 cells, an rat embryonic cardiomyocytes cell line. This effect was dependent on extracellular 〖Ca〗^(2+) but not the 〖Ca〗^(2+) store from sarcoplasmic reticulum because XML had no effect on thapsigargin -induced 〖Ca〗^(2+) release. The effect of XML was inhibited by ML218-HCl but not nimodipine, indicating that XML interacted with T-type 〖Ca〗^(2+) channels but not L-type 〖Ca〗^(2+) channels. Unlike KB-R7943, which is a sodium calcium exchanger inhibitor, XML did not affect [〖Ca〗^(2+)]i in the absence of electric stimulation, implying that XML did not work on sodium calcium exchanger. Ouabain, a sodium-potassium ATPase inhibitor, increased the electrical impulse-induced [〖Ca〗^(2+)]i and the effect of ouabain and XML were not additive, suggesting that the site of action of ouabain and XML was overlapped. Biochemical assay on phosphate concentration showed that XML was able to inhibit the activity of sodium-potassium ATPase. Our study also demonstrated that XML reduced the production of reactive oxygen species in H9c2 cells. Western blotting showed that such antioxidant properties mechanism might involve the increased expressions of antioxidant enzymes including superoxide dismutase 1, superoxide dismutase 2 and heme oxygenase 1. In conclusion, our study has provided evidence that XML increases [〖Ca〗^(2+)]i level by activating T-type 〖Ca〗^(2+) channels and inhibiting sodium-potassium ATPase. The antioxidant effect of XML may also contribute to the cardioprotective effect of XML but further investigation is required. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy

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The purpose of this research was to investigate the feasibility of using high temperature ultrasonic pulses to administer therapeutic hyperthermia treatments independent of changes in blood perfusion and tissue properties. The use of a computer simulation program was used to study the effects of blood perfusion, tissue properties, transducer characteristics, and treatment geometry on the temperature elevation and thermal dose delivered by short high temperature ultrasonic pulses. Experiments were conducted in vitro and in vivo to investigate the effects of blood perfusion changes. Other experiments were carried out in dog thigh muscle to determine the effects of changes in tissue properties. A final study was done where murine melanoma in mice were treated with high temperature ultrasound. Results show that shorter pulse lengths (≤ 2 s) and smaller focal diameters (≤ 3 mm) give practically perfusion independent temperature elevation and thermal dose. Normal fluctuations in tissue properties should not have a significant effect on the treatment provided that proper choice of transducer is made for each individual application. High temperature ultrasonic pulses have also been shown to induce tumor responses. Based on this research, this technique is a feasible means of administering hyperthermia for cancer therapy.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences