A flexibilidade da socialidade presente em muitas espécies sugere que muitos dos traços comportamentais e fisiológicos presentes em grupos sociais complexos possam existir em estado latente em indivíduos de espécies solitárias. Hierarquia de dominância e assimetria reprodutiva são traços característicos de espécies sociais. O hamster Sírio é um excelente modelo para o estudo do estresse social e dos seus efeitos fisiológicos e comportamentais. Na presente pesquisa foram enfocados os efeitos do alojamento em grupo antes e no início da gestação na fêmea de hamster Sírio. Investigou-se se o estresse social produz algum grau de assimetria reprodutiva nesta espécie solitária e se o sucesso reprodutivo e o comportamento materno das fêmeas variam em função do seu status social. Dois experimentos foram realizados envolvendo respectivamente 34 fêmeas de hamster criadas em grupo do desmame até o início do estudo e 76 fêmeas criadas isoladamente. Em cada experimento, um terço dos animais foram alojados em gaiolas individuais, enquanto pares de fêmeas desconhecidas umas das outras eram formados com os outros dois terços. O comportamento dos pares foi observado ao longo de 10 dias para determinar o status social de cada fêmea. Todas as fêmeas foram acasaladas neste período. Quatro dias após o parto, os filhotes foram contados, sexados e pesados e as ninhadas padronizadas a seis filhotes, três machos e três fêmeas. As mães e suas ninhadas foram observadas diariamente durante sessões de 40min e 13 categorias comportamentais foram registradas. No intuito de esclarecer os mecanismos fisiológicos subjacentes à relação entre estresse social e fertilidade, os níveis dos hormônios reprodutivos e dos glicocorticóides foram monitorados ao longo da gestação por métodos não-invasivos, previamente validados, de quantificação dos seus metabólitos nas fezes. Foi demonstrada, pela primeira vez, a adequação de um enzimaimunoensaio e de um conjunto diagnóstico comercial de radioimunoensaio para a quantificação respectiva dos metabólitos fecais de glicocorticóides em hamsters Sírios dos dois sexos e de testosterona no hamster Sírio macho, mas não da fêmea. As variações das concentrações de metabólitos fecais de progesterona, estrógenos e glicocorticóides, refletiram os perfis séricos descritos na literatura para hamsters gestantes. Os resultados mostram que quando fêmeas de hamster Sírio são alojadas individualmente após o desmame, sua fertilidade não é afetada pelo estresse social. Em contraste, quando as fêmeas são criadas em grupo, o estresse social tanto de isolamento como de subordinação a uma fêmea dominante induz um grau significante de assimetria reprodutiva, traço característico de espécies sociais que criam seus filhotes em comunidade. A manutenção de hamsters cativos adultos em grupos parece despertar traços comportamentais e fisiológicos presentes em grupos sociais complexos e que se encontram em estado latente nesta espécie solitária. A socialidade parece flexível no hamster e modulada pelas condições ecológicas. / The flexibility of sociality found in many species suggests that many of the behavioral and physiological mechanisms responsible for highly developed social interactions are present as latent traits, even in species usually considered as solitary. Social hierarchy and reproductive skew are typical features of social species. Syrian hamsters (Mesocricetus auratus) are an ideal model for the investigation of social stress and its physiological, neuroendocrine, and behavioral effects. The present research focused on the effects of group-housing prior to mating and on the first days of gestation of the female hamster. We investigated if social stress produces some degree of reproductive skew in this solitary species, and if female reproductive success varies as a function of social rank. Two experiments were carried out. The first one involved 34 females group-raised from weaning until the beginning of the trial and the second one 76 singly raised females. In each case one third of the animals were singly housed. Pairs of unrelative females were formed with the remaining animals. Pair behavior was observed through 10 days for assessment of the social rank of each female. All females were mated during this period. On day 4 post-partum, pups were counted, sexed, and weighed and litters were culled to six, three males and three females. Litters and dams were observed daily through 40-min sessions and 13 behavioral categories recorded. In order to assess the physiological relationship between social stress and fertility, we monitored reproductive hormones and glucocorticoids of solitary and pair-housed females during pregnancy by utilizing recently established non-invasive methods for measuring the respective hormone metabolites in the feces. The suitability of an enzyme immunoassay and of a commercial radioimmunoassay for respective quantification of fecal glucocorticoid metabolites of hamsters of both sexes and fecal testosterone metabolites in the male but not in the female was proven for the first time. The patterns of fecal progesterone, estrogen, and glucocorticoid metabolites were similar to blood profiles reported in the literature for pregnant hamsters. Our results showed that when female hamsters are singly housed from weaning, social stress did not affect their fertility. However, when females are group-raised, both isolation and subordination stress induced a significant reproductive skew, which is a characteristic feature of cooperative breeders. It seems that group-keeping of adult hamsters evokes social physiological and behavioral mechanisms present as latent traits in this solitary species. As in other rodents, sociability seems flexible in the Syrian hamster and our findings support the idea that social interactions may be a function of ecological conditions.

Chez les hamsters, les jours longs activent la reproduction. Cette activation photopériodique (AP) impliquerait la mélatonine, l’hormone thyroïdienne (HT) et les RFamides hypothalamiques. Si les jours courts inhibiteurs sont maintenus au-delà de 20 semaines, une réactivation photoréfractaire (RP) de l’axe hypothalamo pituitaire gonadotrope (HPG) est déclenchée. Les mécanismes de cette RP sont inconnus. Notre analyse de la cinétique des changements moléculaires induits par l’AP et la RP montre dans les deux cas une inhibition précoce de l’expression de la Désiodinase 3 (Dio3), l’enzyme catabolisant les HT, dans les tanycytes. Associée à une inhibition tardive du transporteur MCT8 des HT, la diminution de Dio3 pourrait créer un pic d’HT dans l’hypothalamus. Dans les 2 activations, Kisspeptine et RFRP3 augmentent plusieurs semaines après l’inhibition de Dio3 et l’activation de l’HPG. Aussi, une inhibition d’RFRP3 lors de l’AP n’affecte pas l’HPG, mettant en cause le rôle du RFRP3. Nous avons donc découvert une inhibition précoce de Dio3 pouvant induire l’activation saisonnière de l’HPG. Le régulateur saisonnier précoce de Dio3 reste à découvrir. / In hamsters, reproduction is activated by long days. This photoactivation (PA) supposedly involves melatonin, hypothalamic thyroid hormones (TH) and RFamide peptides. Maintaining inhibitory short days for over 20 weeks triggers a photorefractory reactivation of the hypothalamo pituito gonadotropic axis (HPG) The mechanisms of this PR are so far unknown. Our cinetic analysis of the dynamic molecular changes in PA and PR revealed a conserved early inhibition of tanycytic deiodinase 3 (Dio3), which catabolizes TH, in both activation mechanisms. Associated with a late decrease of the TH transporter MCT8, the inhibition of Dio3 could generate an early peak of hypothalamic TH. In both activations, RFamide upregulation occurs several weeks after the initial Dio3 inhibition. Also, pharmacological inhibition of RFRP3 during PA does not influence the HPG activity, questioning the role of RFRP3 in HPG activation. We have thus uncovered a so far unreported early Dio3 inhibition that could be sufficient to seasonally reactivate the gonadotropic axis. The seasonal regulator of Dio3 remains to be discovered.

Cette thèse présente les adaptations spécifiques des hibernants ‘food-storing’ qui s’alimentent au cours de l’hibernation, et les conséquences de la qualité du régime alimentaire sur leur cycle annuel. Tandis que les espèces ‘fat-storing’ jeûnent pendant toute l’hibernation, les ‘food-storing’ alternent jeûnes courts et réalimentations. L’adiponectine stimulerait la lipolyse pendant l’hibernation contribuant ainsi à la cétogenèse. Le maintien d’un système digestif fonctionnel conduisant à la sécrétion d’incrétines, permet l’absorption optimale de nutriments lors des courtes euthermies inter-torpeurs. Une absorption accrue de glucose en particulier permettrait de restaurer la glycémie et les réserves de glycogène. Par ailleurs, un régime appauvri en protéines et enrichi en lipides induit un engraissement augmenté en période pré-hibernatoire provoquant une moindre utilisation de la torpeur donc une perte de masse accrue lors de l’hibernation, et une baisse du succès reproducteur. / This thesis presents the specific adaptations of food-storing hibernators that feed during hibernation, and the impact of diet quality on their annual cycle. In contrast to the fat-Storing species which fast during hibernation, the food-storing presents metabolic responses to an alternation of short fasting phases and hyperphagia. These responses involve one hand use of fat reserves during hibernation contributing to ketogenesis, which would be induced by adiponectin. On the other hand, maintaining a functional digestive system leading to the secretion of incretins, permits optimal nutrient absorption in the short inter-torpor euthermia. Increased glucose uptake in particular would restore body reserves to spare. Moreover, a lean protein diet enriched in fat and induces increased in body mass in pre-hibernation period causing reduced use of torpor thus an increased loss of mass during hibernation, and decreased reproductive success.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

A patogenia na leishmaniose visceral (LV) não é totalmente conhecida. Em LV em hamsteres avaliamos a participação de imunoglobulinas nas lesões. IgG foi detectada no sinusóide hepático, nos septos pulmonares e nos capilares glomerulares, em maior intensidade aos 30 e 45 dias pós-infecção (PI); C3 estava ausente, exceto no rim. Os dados não sendo compatíveis com a deposição de imunocomplexo, estudamos ultraestruturalmente a internalização de imunoglobulinas. No fígado e no rim a quantidade de imunoglobulina em célula endotelial era maior aos 30 dias PI em relação ao controle não infectado e no pulmão, aos 30 dias PI em relação aos 60 dias PI. Imunoglobulina internalizada por célula endotelial observada neste estudo na LV em hamsteres, marcadamente aos 30 dias PI, pode ser um mecanismo alternativo de lesão na LV / Pathogenesis of visceral leishmaniasis (VL) is not fully known. In VL in hamsters we evaluated the participation of immunoglobulins in the lesions. IgG was detected in the hepatic sinusoid, in the lung alveolar walls and in the glomerular capillaries in higher intensity at 30 and 45 days post-infection (PI); there were no C3, except in the kidney. Since the data were not compatible with immune complex deposition, we studied ultraestructurally the internalization of immunoglobulins. In the liver and in kidney the amount of immunoglobulin within endothelial cells was greater at 30 days PI than in non infected control, and in the lung at 30 days PI in relation to 60 days PI. Immunoglobulin internalized by endothelial cells observed in VL in hamsters, remarkably at 30 days PI, may be an alternative mechanism of lesion in VL

A Mucosite Oral (MO) é uma consequência debilitante do tratamento oncológico, que pode ser tratada com o uso do laser de baixa potência (LBP). Entretanto, ainda não há consenso na literatura a respeito de parâmetros dosimétricos para o reparo da mucosa oral. Dessa forma, o objetivo do estudo foi comparar diferentes protocolos com laser de baixa potência (FLBP) para o tratamento da MO, através de análises clínicas e histológicas. Quinze hamsters foram usados, em um modelo de indução de MO por 5-Fluorouracil (5-FU) e ranhuras superficiais na mucosa oral, com 7 dias de acompanhamento clínico. Os animais foram divididos em cinco grupos: Controle (C), que recebeu apenas anestesia e o veículo do quimioterápico, Controle-Quimioterapia (CQ) que recebeu anestesia, 5-FU e ranhuras, Laser Protocolo 1 (L1) que recebeu o mesmo do grupo CQ + FLBP 6 J/cm²/0,24 J (um ponto), Laser Protocolo 2 (L2) o mesmo do grupo CQ + FLBP 25 J/cm²/1 J (um ponto) e Laser Protocolo 3 (L3), o mesmo do grupo CQ + FLBP 6 J/cm²/0,96 J (4 pontos de 0,24J). O laser foi utilizado em ?=660 nm, com área do spot de 0,04 cm² e 40 mW de potência. O melhor protocolo de FLBP para manter os graus de MO mais baixos, em relação ao grupo CQ, foi o L1, seguido dos protocolos L2 e L3. Os resultados histológicos demonstraram padrão semelhante entre os grupos L1, L2 e C, com alguns vasos sanguíneos e a presença de um fino epitélio de aspecto contínuo no dia 7. Nossos resultados sugerem que o modo de aplicação do LBP e a energia entregue por área pode interferir na reparação da MO. / Oral mucositis (OM) is a dose-limited debilitating consequence from cancer treatment that could be treated with low level laser therapy (LLLT); however, there is no consensus about its dosimetric parameters for oral mucosa healing. Thus, the aim of this study is to compare different LLLT protocols on the treatment of OM, through clinical and histological analysis. Fifteen hamsters were used, in an induced model of OM by 5-Fluorouracil (5-FU) and superficial scratching in oral mucosa, in seven days of follow-up. The animals were divided into 5 groups: Control (C) which received only anesthesia and chemotherapic vehicle; Control-Chemotherapy (Ch) which received anesthesia, 5-FU and scratches; Laser Protocol 1 (L1) the same as Ch group + LLLT 6 J/cm²/0.24J (one point); Laser Protocol 2 (L2) the same as Ch group + LLLT 25J/cm²/1J (one point); and Laser Protocol 3 (L3) the same as Ch group + LLLT 6 J/cm²/0.96 J (4 points of 0.24J). The laser that was used has ?=660 nm, 0.04 cm² of spot area and 40 mW of power. The best LLLT protocol to maintain lowest OM levels compared to Ch group was L1, followed by L2 and L3. Histological results demonstrated a similar pattern among L1, L2 and C groups, with some blood vessels presence and continuous aspect of a thin epithelium, on day 7. Our results suggest that the application mode of LLLT and the energy delivered per area could interfere in the oral mucositis healing.

高膽固醇血症是產生動脈粥樣硬化的危險因素，本研究旨在探討甾醇的氧化產物和植物化學物質在餵食高膽固醇食金黃地鼠模型中對脂蛋白代謝的影響及其相關機制。 / 本研究包含四個部分。食物中同時含有植物甾醇及其氧化產物。第一部分旨在研究β-穀甾醇（Si）、甾醇(St)、β-穀甾醇氧化產物(SiOP)和豆甾醇氧化產物(StOP)對金黃地鼠血脂的影響。本研究顯示，Si和St組能有效降低血總膽固醇（TC）、非高密度脂蛋白膽固醇（non-HDL-C）和甘油三酯（TAG）的水平，而SiOP和StOP則失去此能力。RT-PCR分析表明，Si和St而非SiOP和StOP，能下調腸道醯基輔酶A：膽固醇醯基轉移酶2（ACAT2）和微粒體甘油三酯轉移蛋白（MTP）的mRNA表達。Si和St而非SiOP和StOP能有效防止動脈粥樣硬，Si和St的動脈弓舒張能力強於對照組和SiOP、StOP組。 / 辣椒鹼是辣椒中的活性成分。本研究第二部分表明，辣椒鹼能降低TC，NON-HDL-C，TAG，而不影響高密度脂蛋白膽固醇。餵養辣椒鹼能增加糞便中總酸性固醇的排泄，此作用有可能是通過上調膽固醇7α-羥化酶（CYP7A1）和下調肝X受體α（LXRα）的基因表達來實驗。辣椒鹼可通過抑制COX-2基因表達來改善內皮依賴性收縮。 / 藍莓含有豐富的抗炎抗氧化劑，例如花青素。本研究第三部分表明，食物中添加0.5和1.0藍莓花青素能導致TC呈劑量效益地降低6-12%，其中還伴隨22-29的中性固醇和41-74%的膽汁酸排泄的增加。RT-PCR分析表明食物中添加的藍莓花青素能下調腸道Niemann-Pick C1 Like 1 (NPC1L1)，ACAT2，MTP， 腺苷三磷酸結合盒轉運體G8(ABCG8)和肝臟3-羥基-3-甲基戊二醯輔酶A還原酶(HMG-CoA　Reductase)的基因表達。 / 芝麻素是芝麻種子中含有抗氧化活性的木脂素類化合物。本研究第四部分表明，在食物中添加芝麻素可有效調控TC和non-HDL-C，同時不影響TAG，並導致非高密度脂蛋白膽固醇與高密度脂蛋白膽固醇比例的下降。這有可能與膽汁酸排泄增加、CYP7A1基因的上調，LXR的下調有關。 / 綜上所述，本研究證實了植物甾醇、辣椒鹼、藍莓花青素和芝麻素降低血膽固醇的能力。與此同時，本研究還表明植物甾醇被氧化後將失去其降低膽固醇的能力。 / Hypercholesterolemia is a major risk factor in the development of atherosclerosis. Functional foods that can lower or regulate cholesterol concentration are of interest to both public and scientific communities. The present study was to investigate the effects of phytosterols, phytosterol oxidation products (POPs), capsaicinoids, blueberry anthocyanins and sesamin on plasma cholesterol concentration using hamsters as a model. / The whole project consisted of four parts. Human diets contain both phytosterols and POPs. Part I was to examine the effect of β-sitosterol (Si), stigmasterol (St), β-sitosterol oxidation products (SiOP) and stigmasterol oxidation products (StOP) on plasma cholesterol concentration. Results showed both Si and St could reduce while SiOP and StOP lost the capacity of lowering plasma total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C) and triacylglycerols (TAG). Real-Time PCR analysis demonstrated Si and St but not SiOP and StOP down-regulated mRNA levels of intestinal acyl CoA: cholesterol acyltransferase 2 (ACAT2) and microsomal triglyceride protein (MTP). In addition, aortas from hamsters given diets containing Si and St relaxed better than those from the control and their corresponding SiOP- and StOP-treated hamsters, suggesting that Si and St not SiOP and StOP were beneficial in improving lipoprotein profile and aortic function. / Capsaicinoids refer to a group of pungent compounds that are the active components found in chili peppers. Part II was to investigate the cholesterol-lowering activity of capsaicinoids and the associated molecular mechanisms. Results demonstrated that capsaicinoids reduced plasma TC, non-HDL-C and TAG with high-density lipoprotein cholesterol (HDL-C) being unaffected. This was accompanied by an increase in the fecal excretion of total acidic sterols, possibly mediated by up-regulation of cholesterol 7α-hydroxylase (CYP7A1) and down-regulation of liver X receptor alpha (LXRα). Capsaicinoids could also improve the endothelium-dependent relaxations and reduce the endothelium-dependent contractions by inhibiting the gene expression of COX-2. / Blueberries are rich in anthocyanins. Results from Part III experiments demonstrated that dietary supplementation with 0.5 and 1.0 % blueberry anthocyanins for 6 weeks decreased plasma TC concentration by 6-12% in a dose-dependent manner. This was accompanied by increasing the excretion of fecal neutral and acidic sterols by 2229% and 4174%, respectively. Real-time PCR analyses demonstrated that incorporation of blueberry anthocyanins into diet down-regulated the genes of intestinal Niemann-Pick C1-like 1 (NPC1L1), ACAT2, MTP, ABCG 8 and hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase. / Sesamin is a major lignan in sesame seed and is known to exhibit antioxidative activity. Part IV was to investigate the mechanism by which sesamin decreased plasma cholesterol concentration. Results clearly demonstrated supplementation of sesamin into diets could favorably reduce serum TC and non-HDL-C with TAG being unaffected. In addition, dietary supplementation of 0.2 or 0.5% of sesamin could cause a significant decrease in the ratio of non-HDL-C to HDL-C. This was accompanied by a marked increase in bile acid excretion and up-regulation of CYP7A1 and down-regulation of LXRα. / In conclusion, phytosterols, capsaicinoids, blueberry anthocyanins and sesamin were beneficial in improving lipoprotein profile in hamsters fed a high-cholesterol diet. However, phytosterols lose the cholesterol-lowering capacity when they are oxidized. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Liang, Yintong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 112-123). / Abstracts also in Chinese. / Chapter Chapter 1 --- General Introduction / Chapter 1.1 --- Cardiovascular diseases --- p.1 / Chapter 1.2 --- Cholesterol --- p.2 / Chapter 1.3 --- Lipoproteins --- p.4 / Chapter 1.4 --- Cholesterol homeostasis --- p.6 / Chapter 1.4.1 --- HMG-CoA reductase --- p.7 / Chapter 1.4.2 --- LDL receptor --- p.9 / Chapter 1.4.3 --- Intestine ACAT2 --- p.10 / Chapter 1.4.4 --- NPC1L1 --- p.11 / Chapter 1.4.5 --- CYP7A1 and LXRα --- p.12 / Chapter 1.4.6 --- SREBP2 --- p.14 / Chapter 1.4.7 --- ABCG5 and ABCG8 --- p.15 / Chapter 1.5 --- Phytochemicals --- p.16 / Chapter 1.5.1 --- Phytosterols --- p.16 / Chapter 1.5.2 --- Capsaicinoids --- p.17 / Chapter 1.5.3 --- Blueberry anthocyanins --- p.19 / Chapter 1.5.4 --- Sesamin --- p.20 / Chapter 1.6 --- Animal model --- p.22 / Chapter Chapter 2 --- Effect of Phytosterols and their Oxidation Products on Lipoprotein Profiles and Vascular Function / Chapter 2.1 --- Introduction --- p.23 / Chapter 2.2 --- Objective --- p.24 / Chapter 2.3 --- Materials and methods --- p.24 / Chapter 2.3.1 --- Preparation of sitosterol oxidation products (SiOP) and stigmasterol oxidation products (StOP) / Chapter 2.3.2 --- Diets --- p.25 / Chapter 2.3.3 --- Hamsters --- p.25 / Chapter 2.3.4 --- Analysis of individual SiOP and StOP in serum and liver --- p.26 / Chapter 2.3.5 --- Analysis of plasma lipoproteins --- p.28 / Chapter 2.3.6 --- Measurement of atherosclerotic plaque --- p.28 / Chapter 2.3.7 --- Analysis of cholesterol in the liver and aorta --- p.28 / Chapter 2.3.8 --- Determination of fecal neutral and acidic sterols --- p.29 / Chapter 2.3.9 --- Real-time PCR analysis of mRNA of liver SREBP2, LDL receptor, HMG-CoA reductase, CYP7A1, LXRα, and small intestine NPC1L1, ABCG5, ABCG8, ACAT2, MTP. --- p.29 / Chapter 2.3.10 --- Western blotting analysis of hepatic SREBP2, LDL receptor, HMG-CoA reductase, LXRα and CYP7A1 --- p.32 / Chapter 2.3.11 --- Vascular reactivity --- p.32 / Chapter 2.4 --- Results --- p.34 / Chapter 2.4.1 --- Composition of SiOP and StOP --- p.34 / Chapter 2.4.2 --- Food intake, body and organ weights --- p.34 / Chapter 2.4.3 --- Plasma TC, HDL, non-HDL ,TAG, Non-HDL-C/HDL-C --- p.34 / Chapter 2.4.4 --- Aortic cholesterol and atherosclerotic plaque --- p.35 / Chapter 2.4.5 --- Liver cholesterol, SiOP and StOP --- p.35 / Chapter 2.4.6 --- Fecal neutral, acidic sterols and cholesterol balance --- p.35 / Chapter 2.4.7 --- Immunoblot and mRNA analysis --- p.36 / Chapter 2.4.8 --- Vascular reactivity --- p.36 / Chapter 2.4.9 --- Role of COX in endothelium-dependent contractions --- p.37 / Chapter 2.5 --- Discussion --- p.50 / Chapter Chapter 3 --- Cholesterol-Lowering Activity of Capsaicinoids Is Mediated by Increasing Sterol Excretion in Hamsters Fed a High Cholesterol Diet / Chapter 3.1 --- Introduction --- p.54 / Chapter 3.2 --- Objective --- p.55 / Chapter 3.3 --- Materials and methods --- p.55 / Chapter 3.3.1 --- Diets --- p.55 / Chapter 3.3.2 --- Hamsters --- p.57 / Chapter 3.3.3 --- Analysis of plasma lipoproteins --- p.57 / Chapter 3.3.4 --- Measurement of atherosclerotic plaque --- p.57 / Chapter 3.3.5 --- Analysis of cholesterol in the liver and aorta --- p.57 / Chapter 3.3.6 --- Determination of fecal neutral and acidic sterols --- p.57 / Chapter 3.3.7 --- Real-time PCR analysis of mRNA of liver SREBP2, LDL receptor, HMG-CoA reductase, CYP7A1, LXRα, and small intestine NPC1L1, ABCG5, ABCG8, ACAT2, MTP --- p.57 / Chapter 3.3.8 --- Western blotting analysis of hepatic SREBP2, LDL receptor, HMG-CoA reductase, LXRα and CYP7A1 --- p.58 / Chapter 3.3.9 --- Vascular reactivity --- p.58 / Chapter 3.4 --- Results --- p.59 / Chapter 3.4.1 --- Food intake, body and organ weights --- p.59 / Chapter 3.4.2 --- Plasma TC, HDL, non-HDL,TAG, Non-HDL-C/HDL-C --- p.59 / Chapter 3.4.3 --- Aortic cholesterol and atherosclerotic plaque --- p.59 / Chapter 3.4.4 --- Fecal neutral, acidic sterols and cholesterol balance --- p.59 / Chapter 3.4.5 --- Immunoblot and mRNA analysis --- p.60 / Chapter 3.4.6 --- Vascular reactivity --- p.60 / Chapter 3.4.7 --- Role of COX in endothelium-dependent contractions --- p.61 / Chapter 3.5 --- Discussion --- p.74 / Chapter Chapter 4 --- Effect of Blueberry Anthocyanins on Lipoprotein Profiles in Hamsters Fed a Cholesterol Diet / Chapter 4.1 --- Introduction --- p.77 / Chapter 4.2 --- Objective --- p.78 / Chapter 4.3 --- Materials and methods --- p.78 / Chapter 4.3.1 --- HPLC analysis of blueberry anthocyanins --- p.78 / Chapter 4.3.2 --- Diet --- p.79 / Chapter 4.3.3 --- Hamsters --- p.80 / Chapter 4.3.4 --- Analysis of plasma lipoproteins --- p.80 / Chapter 4.3.5 --- Analysis of cholesterol in the liver --- p.80 / Chapter 4.3.6 --- Determination of fecal neutral and acidic sterols --- p.81 / Chapter 4.3.7 --- Real-time PCR analysis of mRNA of liver SREBP2, LDL Receptor, HMG-CoA Reductase, CYP7A1, LXRα, and small intestine NPC1L1, ABCG5, ABCG8, ACAT2, MTP --- p.81 / Chapter 4.3.8 --- Western blotting analysis of hepatic SREBP2, LDL Receptor, HMG-CoA reductase, LXRα and CYP7A1 --- p.81 / Chapter 4.4 --- Results --- p.82 / Chapter 4.4.1 --- Food intake, body, and organ weights --- p.82 / Chapter 4.4.2 --- Plasma TC, HDL-C, non-HDL-C, and TAG --- p.82 / Chapter 4.4.3 --- Liver cholesterol concentration --- p.82 / Chapter 4.4.4 --- Fecal total sterols and apparent sterol retention --- p.82 / Chapter 4.4.5 --- Immunoblot and mRNA analysis --- p.83 / Chapter 4.5 --- Discussion --- p.92 / Chapter Chapter 5 --- Effect of Sesamin on Lipoprotein Profiles in Hamsters Fed a high Cholesterol Diet / Chapter 5.1 --- Introduction --- p.95 / Chapter 5.2 --- Objective --- p.95 / Chapter 5.3 --- Materials and methods --- p.96 / Chapter 5.3.1 --- Diets --- p.96 / Chapter 5.3.2 --- Hamsters --- p.96 / Chapter 5.3.3 --- Methods --- p.97 / Chapter 5.4 --- Results --- p.98 / Chapter 5.4.1 --- Food intake, body and organ weights --- p.98 / Chapter 5.4.2 --- Plasma TC, HDL-C, non-HDL-C ,TAG, Non-HDL-C/HDL-C --- p.98 / Chapter 5.4.3 --- Liver cholesterol --- p.98 / Chapter 5.4.4 --- Fecal neutral, acidic sterols and cholesterol balance --- p.98 / Chapter 5.4.5 --- Immunoblot and mRNA analysis --- p.99 / Chapter 5.5 --- Discussion --- p.109 / References --- p.112

Pancreatic cancer kills over 1700 people each year in Australia. In 2000, there were 1908 new cases diagnosed and it remains one of the least treatable malignancies. In the USA, it was the fourth leading cause of cancer death in 2004, with 31,860 new cases and 31,270 recorded deaths. Photodynamic therapy (PDT) is a novel, potentially useful treatment for locally advanced pancreatic cancer with only limited research and clinical work addressing this until now. PDT induces non-thermal, cytotoxic and ischaemic injury to a targeted volume of tissue. During PDT, a photosensitizer is activated by non-thermal light in the presence of oxygen, generating cytotoxic oxygen species and inducing cellular injury and microvascular occlusion. The aim of this thesis was to conduct an animal safety study using two second generation photosensitizers, talaporfin sodium and verteporfin, to assess the risks of pancreatic PDT by looking at injury to organs adjacent to the pancreas and assessing recovery from PDT treatment of the pancreas. The Syrian Golden hamster animal model was used to compare the results of this research to previous work by other authors. The study design incorporated a number of additional experiments, including quantitative tissue fluorescence techniques, plasma level analysis and histopathology techniques. The methods for the animal safety study were similar to the approach used in the clinical setting and provided vital data on the likely risks and side effects of phototherapy in humans. The first study, looking at talaporfin sodium, found likely risks of duodenal injury, gastric injury and death with a limited effect on normal pancreas at photosensitizer doses likely to be employed for pancreatic cancer PDT. The second study, using verteporfin, found similar results with a more potent effect on the normal pancreas at studied drug doses. Both agents had short drug-light intervals, ranging from 15 minutes to 2 hours, reducing the need for pre-treatment hospitalization and short photosensitivity periods of about one to two weeks. Some animals suffered minor cutaneous photosensitivity injuries. A human pancreatic cancer PDT pilot study is feasible and the risks and complications should be acceptable.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.