published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

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published_or_final_version / Community Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Public Health / Master / Master of Public Health

Obesity is closely related to many medical complications such as type 2 diabetes, hypertension and heart failure. Obesity and other factors, including elevated blood glucose levels, hypertension, and dyslipidemia, constitute a constellation of symptoms known as the metabolic syndrome, which are the risk factors for coronary artery disease. Lipocalin-2 is a pro-inflammatory adipokine causally involved in the development of obesity-associated metabolic and cardiovascular diseases. Recent clinical and experimental evidences demonstrate an association between augmented circulating lipocalin-2 and cardiac dysfunction. However, little is known about the detailed roles of lipocalin-2 in regulating pathophysiological functions of the heart. The present study was designed to compare the heart functions of mice with normal (WT) or deficient lipocalin-2 (Lcn2-KO) expression and to examine the molecular mechanisms underlying lipocalin-2-mediated deteriorated effects in hearts. Echocardiographic analysis revealed that the myocardial contractile function was significantly improved in hearts of Lcn2-KO mice, under both standard chow and high fat diet conditions. The heart function before and after I/R injury (20-min of global ischemia followed by 60-min of reperfusion) was assessed using the Langendorff perfusion system. Compared with WT littermates, hearts from Lcn2-KO mice showed improved functional recovery and reduced infarct size following I/R. These phenomena can be observed in mice under both standard chow and high fat feeding conditions. Under baseline condition, the mitochondrial function of hearts from Lcn2-KO mice was significantly enhanced, as demonstrated by biochemical analysis of respiratory chain activity, markers of biogenesis and oxidative stress, as well as electron microscopic investigation of the mitochondrial ultrastructure. Acute or chronic administration of lipocalin-2 impaired cardiac functional recovery to I/R and dampened the mitochondrial function in hearts of Lcn2-KO mice. These effects were associated with an extensive modification of the fatty acyl chain compositions of intracellular phospholipids. In particular, lipocalin-2 facilitated the redistribution of linoleic acid (C18:2) among different types of phospholipid, including cardiolipin, which is exclusively located in the mitochondria inner membrane. The direct effects of lipocalin-2 on both H9c2 and NCM cells were also examined. TUNEL assay and flow cytometry analysis demonstrated that lipocalin-2 treatment promoted apoptosis in cardiomyocytes. Lipocalin-2 induced an early phase of phosphatidylserine exposure, followed by Bax-translocation and caspase-3 cleavage. The results collectively suggested that lipocalin-2 initiated the intrinsic mitochondria-mediated apoptotic pathway. In the hearts of Lcn2-KO mice, significantly reduced number of apoptotic cells was observed after I/R injury. In conclusion, lacking of lipocalin-2 improved heart function recovery during I/R injury via mitochondrial function restoration, phospholipids remodeling, and inhibition of cardiomyocytes apoptosis. / published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Background: Research studies in recent years suggested possible role of dark chocolate in preventing cardiovascular diseases due to its high flavonal and procyanidins contents. Whether there is clear clinical benefit and the mechanisms mediating such benefits is controversial. Objective: This systematic review aims to comprehensively examine the current clinical evidence regarding effectiveness and the possible mechanisms of chocolate in reducing the risk and / or surrogate markers of cardiovascular diseases. Methods: Comprehensive electronic literature search was performed using Ovid, Medline and Cochrane database. Only English language literatures published during year 1950 - 2010 were reviewed. All intervention studies and observational studies of adult human subjects taking white or dark chocolate in relation to outcomes of cardiovascular risk were included. All review articles and meta-analysis were also included. Clinical diagnosis of cardiovascular disease and surrogate markers including blood pressure, vascular endothelial function as measured by flowed mediated vasodilation, and blood biomarkers such as lipid profile were studied as outcome variables. Results: The review outlines recent observational and interventional studies and meta-analysis to give an overview of the topic. For observational studies, a cohort studies and two case control studies were found. The observational studies showed that dark chocolate consumption was inversely associated with blood pressure, cardiovascular mortality and C-reactive protein. All interventional studies searched showed that dark chocolate increased FMD and improved platelet function. However, the effects of cocoa on intermediate outcomes such as blood pressure, antioxidant capacity and inflammatory marker changes were inconsistent among interventional studies. Three interventional studies indicated that there was a dose-dependent improvement in immediate outcome variables after 1 month or even 2 hours acute consumption of dark chocolate with procyanidins or cocoa drink with flavonol. However, publication bias and potential conflict of interests may be a potentially important factor in interpreting study results in the current literature. Conclusions: There are some clinical and scientific evidences that consumption of dark chocolate produces positive cardiovascular benefits. A small amount of dark chocolate may be good for the heart. However, gaps in our knowledge such as a lack of long-term RCT in clinical outcomes must be filled in before recommending habitual dark chocolate consumption for reduction of cardiovascular risk. / published_or_final_version / Community Medicine / Master / Master of Public Health

Background Over the past few years, results refuting the causal role of HDL cholesterol (HDL-c) have been reported by a number of randomized controlled trials (RCTs) testing different ways of modifying HDL-c. Results from Mendelian randomization studies showed no difference in cardiovascular disease (CVD) risk among individuals with genetically different serum levels of HDL-c. The causal role of HDL-c in CVD is thus uncertain, raising the question as to whether HDL-c is a worthwhile target of public health interventions and medical treatments. The objective of these meta-analyses is to explore whether changes in HDL-c are symptomatic of prior causes instead of being a causal factor for CVD by first identifying two possible candidates—androgens and zinc—for the investigation of associations. Experimental evidence would then be investigated for whether either of them might underlie (i.e. confound) the observed association of HDL-c with CVD risk factors. Methods This study followed the PRISMA statement. A literature search was conducted through PUBMED, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. Keywords of “androgens/testosterone”, “HDL”, “high-density lipoprotein”, “lipid”, “cholesterol”, “lipoprotein”, “CVD”, “cardiovascular”, “heart”, “cardiovascular disease” were used with the search period limited to January 2000 – June 2013 with only human RCTs conducted and reported in English. For locating studies concerning the effect of zinc, the keyword “zinc” was used instead of “androgens/testosterone”. Inclusion and exclusion criteria were applied during study screening and selection. The Cochrane Collaboration’s tool for assessing risk of bias was used for quality assessment. Heterogeneity across included studies was measured using I2 statistic and publication bias was assessed via funnel plots and the Begg’s Rank Correlation test. The “trim and fill” method was also used for the correction of funnel plot asymmetry. The meta-analyses were performed using The Comprehensive R Archive Network Program (Version R 3.0.0), using the function “metacont” from the “meta” package, where the pooled intervention effects were displayed using forest plots, with inverse variance weighting and random effects model. Results A total of twelve and ten RCTs were identified and included in the meta-analyses of androgens and zinc respectively. There were no consistent beneficial effects of androgens on CVD observed, as the results from CVD surrogate markers were inconclusive, despite showing significant overall reduction in HDL-c levels. However, as current findings suggest that lower HDL-c levels are associated with higher cardiovascular risk, it is possible that androgens may increase that risk by influencing HDL metabolism. On the other hand, zinc was associated with healthier CVD profile. This supports the notion of zinc as a cardioprotective agent. Nonetheless, conclusion failed to be drawn concerning the effect of zinc on HDL-c as there were contradictory results across included studies. Conclusion The meta-analyses suggest that androgens could be a factor which lowers HDL-c and thus increases cardiovascular risk, rather than HDL-c being the direct causative agent. This research may serve as a template for more extensive search for other potentially better candidates in this new study focus in cardiovascular epidemiology. / published_or_final_version / Community Medicine / Master / Master of Public Health

Background: Cardiovascular disease is the leading cause of mortality and morbidity in the world and has something to do with daily diet. The polyphenol is the most abundant compound in daily diet, including grape. The red wine was rich in polyphenol because of composing much grape. Early study has already confirmed the “French Paradox” in cardiovascular protection power, which shed light on the dietary modulation on disease. Objective: The main objective of the study was to evaluate the effect of products containing polyphenol such as red wine extract, grape juice and grape extract tablets or powder on cardiovascular disease risk factors. It mainly examined relationship between polyphenol and serum lipid in addition to blood pressure. Methods: Studies working on effects of grape extract products on cardiovascular disease were searched from electronic resources MEDLINE and EMBASE. Nine clinical controlled trials were identified through PubMed and Ovid. CONSORT guideline and Jadad Score were used to appraise the quality of trials. Weighing two assessment guidelines, a total of three studies were in good quality, one was in bad quality while the rest four were fair to middle. Results: The changes before and after intervention on serum lipid and blood pressure were contradictory. Some studies found polyphenol was statistically significant protective factors, while some did not find it siginificant but still showed a protective effect. One study found polyohenol had no effect on cardiovascular disease risk factors. Conclusion: The prevention of polyphenol was not consistent in nine trials and there is no sufficient and strong evidence supporting its cardiovascular protection effect given that the study design of each trial differed. It was not recommeded to use grape polyphenol as cardiovascular protect products. There were limitations and weakness of current study on the association of polyphenol and cardiovascular disease. Further research on this topic is required, both in vivo and in vitro. / published_or_final_version / Public Health / Master / Master of Public Health

Pluripotent stem cells hold great promise in regenerative medicine. Theoretically, a variety of tissues can be generated from this progeny. The production of tailor-made stem cells for individualized patient treatment is the ultimate goal of stem cell based therapy. Human induced pluripotent stem cells (iPSCs) hold the precious key to success and promote the clinical application of stem cells. By reprogramming somatic cells, pluripotent stem cells can be generated in a patient-specific manner and subsequently differentiated into specific tissue for regeneration. Nonetheless exposure of hiPSCs to animal feeder cells and serum during generation and maintenance imposes a risk of transmitting animal pathogens to human subjects, thus hindering their potential therapeutic application. In addition, the efficacy of iPSC generation is < 1% of total somatic cells used. The first part of the study focused on the development of improved methods to produce a more efficient xenogen-free culture system to produce more clinically compatible iPSCs. Specific tissue or cells derived from stem cells may offer a solution and cell therapy using endothelial cells and their progenitors may be possible in treatment of severe cardiovascular diseases. In theory, endothelial cells can be generated from different sources of progenitor cells although no direct comparison of these various derived endothelial cells (ECs) has been reported. Thus in the second part of the study, the functional and physiological properties of BM, ESC and iPSC-ECs will be evaluated to determine their therapeutic potential in ischemic disease. A mouse hind limb ischemia model was used to assess and monitor neovascularization by the derived ECs. The results can provide further insight to evaluate the possibility of using iPSCEC as the cell source for patient-specific treatment. Use of pluripotent stem cells is a promising approach in therapeutic angiogenesis although numerous hurdles continue to hamper their widespread clinical use. Conditioned medium derived from progenitor cells may be another possible strategy in the treatment of ischemic diseases such that direct cell transplantation is avoided. Conditioned media produced from ex vivo culture of endothelial cells contain a combination of angiogenic factors that can be applied to promote neovascularization in ischemic tissue. Nonetheless the efficacy of this angiogenic application is unknown. The third part of the study focused on the potential application of EC-derived conditioned media in the treatment of ischemic disease using a mouse hind limb ischemia model. Some cardiovascular risk factors such as diabetes might affect endothelial cell function such that autologous application of ECs and their conditioned media is not feasible. A human embryonic stem cell line may offer and alternative means to obtain stable quality ECs and conditioned medium for therapeutic use. In summary, advances in stem cell technology hold great promise for the treatment of cardiovascular disease, further improved by the generation of patient-specific stem cells using iPSC technology. Vascular cells can be generated from different sources of stem cells with similar angiogenic properties and may be used in the treatment of ischemic diseases. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy