Breast cancer is the most common malignant cancer in western countries. It can be classified into various types/stages according to patient age, tumor size, histological grade or hormone receptor status. Obesity is a well-known risk factor of breast tumor. Studies have shown that overweight or obese postmenopausal women have a threefold higher risk to develop breast cancer in comparison to their lean or normal counterparts. There are many mechanisms that can link obesity with breast cancer and one of the major contributors is adipokines. The main focus of this study is adiponectin. Many cellular and animal studies have illustrated the inhibitory action of adiponectin on breast cancer cell proliferation. In this study, the effect of complete loss of adiponectin expression on breast cancer development in Mouse Mammary Tumor Virus-polyomavirus middle T antigen(MMTV-PyVT)mice [PyVT(+/-)]will be investigated. Mice with [ADN(+/+)]or without [ADN(-/-)] adiponectin gene were used for comparison. It was found that PyVT(+/-)ADN(-/-)mice had earlier tumor onset time and larger tumor volume than PyVT(+/-)ADN(+/+) mice. Histological analysis has demonstrated that increased and more dispersed metastasis existed in lung tissue of PyVT(+/-)ADN(-/-)mice in comparing with PyVT(+/-)ADN(+/+)mice. The aggressiveness of adiponectin deficient tumor was preserved after implantation into immune-deficient mice. Gene expression and protein expression studies of PyVT tumor have indicated a different expression level and pattern of two important molecules: P63 and YY1. In conclusion, tumor developed under microenvironment of adiponectin deficient will give rise to a more aggressive tumor. This tumor consistsof modified genotypes and phenotypes that are permanent and can be preserved after re-implantation into immuno-compromised mice. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

Production of hormones in the ovary is controlled by endocrine, paracrine, autocrine and intracrine influences. Similar controls may exist in the placenta. I wished to investigate the involvement of second messengers in the action of hormones in control of hormonogenesis in rat ovary and human placenta. The second messengers involved in the action of gonadotropin-releasing hormone (GnRH) and prostaglandin (PG) F₂[formula omitted] were investigated in rat granulosa and luteal cells. As well, the endocrine role of GnRH in the placenta and the possible second messengers involved were investigated. Monolayer cultures of rat granulosa and luteal cells and human placental cells were prepared. Rat granulosa cells were mechanically dispersed; rat luteal cells were enzymatically dispersed with collagenase and DNase. Rat granulosa cells were treated during the first 24 hours in culture; rat luteal cells were treated up to 3 days after dispersion. Radioimmunoassay of medium was used to determine the effect of treatments on hormone production. Studies which examined the effect of hormones on the intracellular free calcium concentration ([Ca²⁺]i) in single cells using the calcium sensitive fluorescent dye, Fura-2, were done in monolayer rat granulosa and luteal cell cultures. Human placental cells, from first trimester and term placentae, were dispersed using trypsin-DNase or collagenase-DNase. Cells were cultured for 2 days prior to treatment. The effects of treatments on production of steroid (progesterone and estrogen), glycoprotein (human chorionic gonadotropin; hCG) and protein (human placental lactogen; hPL) hormones were determined by radioimmunoassay of the medium. In rat granulosa and luteal cell cultures, I examined the effect of a number of hormones and second messengers. Effects of follicle-stimulating hormone (FSH), luteinizing hormone (LH), cyclic adenosine monophosphate (cAMP), GnRH and PGF₂[formula omitted] on ovarian hormonogenesis have been previously reported. Changes in cytosolic free calcium concentrations ([Ca²⁺]i) in response to PGF₂[formula omitted] were measured in single rat granulosa and luteal cells. I found that in 34% of granulosa cells, and 53% of luteal cells, there was a 3 to 4 fold increase in resting [Ca²⁺]i within 30 seconds of administration of PGF₂[formula omitted]. Many cells which responded to PGF₂[formula omitted] also responded to GnRH (39% of granulosa cells; 67% of luteal cells). The immediate source of the increased [Ca²⁺]i appeared to be common intracellular stores. No change in hormone production in response to GnRH in placental cell cultures was seen. Trypsin dispersion may have damaged cell surface receptors, therefore the effect of second messengers on hormone production in these cultures was examined. In term and first trimester trophoblast cultures, I observed the following effects with 8-bromo-cyclic adenosine monophosphate (8-br-cAMP): inhibited estrogen production from the supplied androgen precursors; stimulated hCG production; stimulated hPL production in first trimester placental cell cultures (hPL was not measured in enough term cultures to determine the effect of 8-br-cAMP), and stimulated progesterone production. I also investigated the effects of activators and inhibitors of the phosphoinositide (PtdIns(4,5)P₂) breakdown second messenger pathway (TPA, A23187, arachidonic acid); no effects of these agents were seen. Other hormones suspected of having endocrine, paracrine or autocrine effects in the placenta were tested without effect. I conclude that GnRH and PGF₂[formula omitted] cause increases in [Ca²]i in rat ovarian cells, from common intracellular stores of calcium, and that the production of hormones by the human placenta may be under regulation of an agent or agents which induce production of cAMP. / Medicine, Faculty of / Obstetrics and Gynaecology, Department of / Graduate

by Psyche, Sui-Ki Fong. / Thesis submitted in: December 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 129-135). / Abstract also in Chinese. / Abstract in Chinese --- p.1 / Abstract in English --- p.2 / Chapter Chapter I. --- Introduction --- p.4 / Chapter I.1. --- Structure and functions of the uterus --- p.4 / Chapter I.1.1. --- Uterus: Gross structure and functions --- p.4 / Chapter I.1.2. --- Uterine wall: functional layers --- p.6 / Chapter a. --- Myometrium --- p.6 / Chapter b. --- Endometrium --- p.6 / Chapter I.1.3. --- Uterine functions : regulatory systems --- p.10 / Chapter a. --- Nervous regulation --- p.10 / Chapter b. --- Hormonal regulation --- p.11 / Chapter I.1.4. --- Uterotrophic agents : selected examples --- p.12 / Chapter a. --- Adrenaline and noradrenaline --- p.12 / Chapter b. --- Prostaglandin E2 and F2α --- p.15 / Chapter I.2. --- Endometrial epithelium and uterine fluid composition --- p.19 / Chapter I.2.1. --- Uterine fluid composition --- p.19 / Chapter I.2.2. --- Regulation of uterine fluid volume and composition --- p.19 / Chapter I.2.3. --- Role of endometrial epithelium in the regulation of uterine fluid composition --- p.20 / Chapter I.3. --- Pioneering works on ion transport across the endometrium --- p.21 / Chapter I.4. --- Objectives of study --- p.23 / Chapter Chapter II --- Materials and Methods --- p.24 / Chapter II.1. --- Materials --- p.24 / Chapter II.1.1. --- Culture media and enzyme --- p.24 / Chapter II 1.2. --- Drugs --- p.24 / Chapter II 1.3. --- Chemicals --- p.25 / Chapter II 1.4. --- Animals --- p.25 / Chapter II.2. --- Methods --- p.25 / Chapter II.2.1. --- Preparation of permeable support for cell culture --- p.25 / Chapter II.2.2. --- Preparation of culture medium for cell culture --- p.26 / Chapter II.2.3. --- Cell isolation and culture --- p.28 / Chapter II.2.4. --- Preparation of electrodes --- p.29 / Chapter II.2.5. --- Preparation of solutions --- p.29 / Chapter II.2.6. --- The short-circuit current technique --- p.31 / Chapter a. --- Experimental setup --- p.32 / Chapter b. --- Transepithelial conductance and resistance measurements --- p.37 / Chapter c. --- Experimental procedure --- p.37 / Chapter II.2.7. --- Statistics --- p.38 / Chapter Chapter III. --- Results --- p.39 / Chapter III.1. --- Electrogenic ion transport across the cultured mouse endometrial epithelium --- p.39 / Chapter III.2. --- Stimulation of anion secretion by β-adrenoceptors --- p.54 / Chapter III.3. --- Regulation of anion secretion by prostaglandin E2 --- p.78 / Chapter III.4. --- Cellular mechanisms of adrenaline-stimulated anion secretion --- p.98 / Chapter Chapter IV. --- General Discussion --- p.123 / Chapter Chapter V. --- Reference --- p.129

Preliminary analyses of three kinds of promoter activity showed that a-actin gene promoter was chosen to initiate the hormone transcription for the first consideration. We have fused the cDNAs encoding the intact somatolactins in frame to a zebrafish a-actin gene promoter to generate transgenic zebrafish lines co-injected with a GFP protein driven by the same promoter. The transgenic zebrafish were selected from GFP expression and confirmed by genomic PCR and Southern blot analysis, then maintained as transgenic founders. Measurement of the transgenes' expressions and the expressions of marker genes in different pathways by using real-time PCR provided a general understanding of SLs' actions. The data obtained indicated that the over-expressing of SLalpha and SLbeta in vivo significantly enhance the transcriptions of the insulin-like growth factors, IGF1 (5.46-fold and 6.77-fold), IGF2a (4.38-fold and 4.35-fold) and IGF2b (2.83-fold and 3.94-fold), but down-regulated IGF3 (a novel member found specifically in gonad) in larvae. However, the stimulation by administration of recombinant proteins (SLalpha and SLbeta) only showed a slight induction of the mRNA levels of IGFs (IGF1, IGF2a and IGF2b) on ZFL cells in vitro. / Somatolactin (SL) is a novel member of pituitary polypeptide hormone found only in fish; it shares significant structural homology with prolactin and growth hormone. Since somatolactin receptor (SLR) was first defined as GHR1 and orthologous to the growth hormone receptor GHR2, SL and GH may share similar actions in growth and development. Recently, two SLs have been identified as SLalpha and SLbeta with similar structures, freshwater fish have these two isoforms found in the same species and only one isoform (SLalpha) is found in marine species. The two isoforms of SL may have different functions and physiological actions. To investigate the roles of SLs on vertebrate development and embryogenesis, we generated transgenic fish models with "all zebrafish" elements in origin to study the physiological functions of SLs in zebrafish. / The ectopic expression of somatolactins also results in up-regulating gene expression of insulin, leptin, sterol regulatory element binding protein 1 (SREBP1) and fatty acid synthase (FAS), as well as the expression of vitellogenin and melanocyte-stimulating hormone (MSH) levels while causing reduction of catalase (CAT) and glutathione S-transferase (GST) levels in larvae. The results here represent the similar function between SLalpha and SLbeta and reveal more details in fish of the endocrinology system involvement in growth development, glucose synthesis, lipid metabolism, reproduction, pigmentation and antioxidant defense system through the actions of SLs. / Three different gene promoters of zebrafish have been isolated to initiate the ectopic expression of somatolactins in vivo, which including a constitutional beta-actin gene promoter, a liver specific transferrin gene promoter and a zinc ion inducible metallothionein (MT) gene promoter. The promoter activities were tested in fish cell-line by using luciferase reporter assay. In MT gene promoter, two alleles of a zebrafish metallothionein II gene (zMT-II) promoter (zMT-IIA and zMT-IIB) containing 10 MREs in the 5'-flanking region (1,514 bp) were identified in zebrafish. These putative MREs were confirmed via electrophoretic mobility shift assay (EMSA) to have binding activities from the cellular and nuclear extracts of a zebrafish cell line, ZFL. Transient gene expression studies using zebrafish liver (ZFL) cell lines also confirmed that the most distal cluster of MREs contributed to the maximal induction of zMT-IIA activity by Zn2+ and the Zn 2+ induction was dose-dependent. EMSA also identified transcription factor(s) of two different sizes from the cytoplasmic and nuclear extracts of the ZFL cells that were able to bind with the MREs, but no increase in MRE binding was detected in the extracts of these cells after Zn2+ or Cd2+ treatment, compared with untreated control cells. The mechanisms of MT gene transcription induction via metal ions are discussed herein. / Wan, Guohui. / Adviser: Chan King Ming. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 139-163). / 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, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Background: Leptin is a new adipose-derived hormone discovered in 1994. It is vital in energy balance and weight regulation in humans. During pregnancy the placenta is an extra source of leptin. The role of leptin in pregnancy is not established. This has generated a lot of interest in leptin research in pregnancy. Leptin is being examined in pathological states that may have origin in adipose tissue and the placenta such as pre-eclampsia, intrauterine growth restriction and obesity. Aim and Method: This study measured concentrations of serum leptin in Black African women during late pregnancy in 68 women with pre-eclampsia, 92 healthy normotensive pregnant women and in 32 healthy non-pregnant women. In each group leptin levels were compared between obese (body mass index, BMI = or > than 30 kgm-2) and lean women. Serum leptin concentrations were measured by radioimmunoassay (RIA) technique. Results: Serum leptin levels were higher in pregnancy compared to non-pregnant women (26.66+/-16.13 ng/ml, 25.89+/-15.83 ng/ml vs 17.97+/-11.98 ng/ml, p=0.02). This is due to firstly, the extra fat accumulated as part of the maternal adaptation to pregnancy and secondlv, to the placenta-derived leptin. Other pregnancy hormones such as insulin, hcG, prolactin and oestrogen may modulate the serum levels of leptin in pregnancy. Simple anthropometric parameters (weight, BMI, circumferences of the mid upper arm (MAC), waist (WC), hip (HC), and thigh (TC) and waist-hip ratio (WHR)) were used to explore the relationship between leptin concentrations and obesity. All the parameters showed a positive correlation with serum leptin concentration in all the groups with the exception of WHR. Weight and BMI showed the greatest correlation both in pregnant (r=0.61 and r=0.58, respectively, p<0.001) and non-pregnant (r=0.74 and 0.79, respectively, p<0.001) women. However we did not find a significant difference in the concentrations of leptin between women with and those without pre-eclampsia (26.66 ng/ml vs 25.89 ng/ml, p=0.95). This probably means that adiposity is the predominant factor influencing levels of leptin in pregnancy. The other factors mentioned above play only a minor role. Indeed the mean serum leptin levels were higher in obese compared to lean women in both pregnant and non-pregnant women. Conclusion: Pregnancy is a hyperleptinaemic state. There is no difference in serum leptin levels between women with pre-eclampsia and healthy normotensive pregnant women. Serum leptin concentration is largely determined by the degree of adiposity both in and outside pregnancy. / Thesis (M.Med.)-University of Natal, Durban, 2001.

Includes bibliographical references (leaves 159-213) Shows that IGF-I peptides are effective in diminishing post-surgical catabolism and enhancing adaptive gut hyperplasia in rats recovering from massive small bowel resection.

xxiii, 222 leaves : ill., plates ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Shows that IGF-I peptides are effective in diminishing post-surgical catabolism and enhancing adaptive gut hyperplasia in rats recovering from massive small bowel resection. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Science, 1992

O uso de álcool entre mulheres é uma questão atual e preocupante, face a maior vulnerabilidade destas aos danos hepáticos, cerebrais, entre outros, quando comparadas aos homens com padrões semelhantes de consumo. Sendo assim, investigaram-se as possíveis variações na farmacocinética do etanol em mulheres, considerando duas fases do ciclo menstrual (pré-folicular e lútea), bem como o uso de anticoncepcionais orais (AO). Participaram voluntários dos sexos feminino (n=22) e masculino (n=14), administrando-lhes 0,3 g/kg de etanol, na forma de uísque. Os resultados indicaram: a) os parâmetros farmacocinéticos do etanol não variam em função do ciclo menstrual (fase pré-folicular e lútea); b) as mulheres que tomavam AO levam menos tempo para atingir a concentração máxima e eliminam o etanol mais rapidamente do que as que não faziam uso; c) não houve diferença nos parâmetros farmacocinéticos entre o grupo de homens e o de mulheres que utilizavam AO, porém os homens apresentam maior velocidade de eliminação do que as mulheres que não faziam uso e d) os parâmetros farmacocinéticos relacionados com a biodisponibilidade (área sob a curva) e com o volume de distribuição não apresentaram diferenças entre os grupos analisados. / After drinking equivalent amounts of alcohol, women appear to be more vulnerable than men to many adverse consequences of alcohol use, including liver and brain damage. This study investigated the influence of menstrual cycle and female sex steroids levels on ethanol pharmacokinetics, as a possible mechanism for these effects. Twenty-two female and 14 male volunteers were given a moderate dose of ethanol (0.3 g/kg) in the morning after an overnight fast. The results indicated: a) no evidence that the tested menstrual cycle phases (pre-follicular and luteal) significantly influence ethanol pharmacokinetics; b) the time required to reach peak BAC was shorter and the ethanol elimination rate was increased for women taking oral contraceptives (OC) as compared to women not taking them; c) there is no difference on ethanol pharmacokinetics between men and women taking OC, but men showed increased ethanol elimination rate compared to women not taking OC; d) no gender-related differences relating to bioavailability of ethanol were found.

O uso de álcool entre mulheres é uma questão atual e preocupante, face a maior vulnerabilidade destas aos danos hepáticos, cerebrais, entre outros, quando comparadas aos homens com padrões semelhantes de consumo. Sendo assim, investigaram-se as possíveis variações na farmacocinética do etanol em mulheres, considerando duas fases do ciclo menstrual (pré-folicular e lútea), bem como o uso de anticoncepcionais orais (AO). Participaram voluntários dos sexos feminino (n=22) e masculino (n=14), administrando-lhes 0,3 g/kg de etanol, na forma de uísque. Os resultados indicaram: a) os parâmetros farmacocinéticos do etanol não variam em função do ciclo menstrual (fase pré-folicular e lútea); b) as mulheres que tomavam AO levam menos tempo para atingir a concentração máxima e eliminam o etanol mais rapidamente do que as que não faziam uso; c) não houve diferença nos parâmetros farmacocinéticos entre o grupo de homens e o de mulheres que utilizavam AO, porém os homens apresentam maior velocidade de eliminação do que as mulheres que não faziam uso e d) os parâmetros farmacocinéticos relacionados com a biodisponibilidade (área sob a curva) e com o volume de distribuição não apresentaram diferenças entre os grupos analisados. / After drinking equivalent amounts of alcohol, women appear to be more vulnerable than men to many adverse consequences of alcohol use, including liver and brain damage. This study investigated the influence of menstrual cycle and female sex steroids levels on ethanol pharmacokinetics, as a possible mechanism for these effects. Twenty-two female and 14 male volunteers were given a moderate dose of ethanol (0.3 g/kg) in the morning after an overnight fast. The results indicated: a) no evidence that the tested menstrual cycle phases (pre-follicular and luteal) significantly influence ethanol pharmacokinetics; b) the time required to reach peak BAC was shorter and the ethanol elimination rate was increased for women taking oral contraceptives (OC) as compared to women not taking them; c) there is no difference on ethanol pharmacokinetics between men and women taking OC, but men showed increased ethanol elimination rate compared to women not taking OC; d) no gender-related differences relating to bioavailability of ethanol were found.