The plant Garcinia gardneriana (Planch. & Triana) Zappi, popularly known in Brazil as "bacupari" has traditionally been used for various types of inflammatory diseases and the evaluation of their chemical composition, mainly of leaves, has resulted in biflavonoids as major compounds. These phenolic compounds have shown anti-inflammatory activity validating the popular use of the plant. In this work was isolated from dried branches of Garcinia gardneriana the biflavonoids: morelloflavone, that is an naringenin covalently linked to luteolin, Gb-2a which is an naringenin linked to eriodictyol and Gb-2a- 7-O-glucose. These compounds have been previously evaluated in various activities such as anti-inflammatory and anti-antioxidants but there is no report of its activity as enzymatic inhibitors. However, the monomers that form it, have been evaluated in the inhibition of aromatase and antidepressant activity with positive outcome, which commonly are used MAO-A inhibitors. In the isolation process were also founded terpenoid compounds as lupeol and friedelin The isolated and purified biflavonoids were used to evaluate enzyme inhibition "in vitro" in monoamine oxidases (MAO-A MAO-B) and aromatase. The compounds showed a positive response even of IC50 5,47 μM and 1,35 μM for MAO-A inhibition of and aromatase enzyme respectively; discovering a way for a new proposal to link both enzymes for treatment of hormone-dependent cancers and anxiety and depression disorders. / La planta Garcinia gardneriana (Planch. & Triana) Zappi, popularmente conocida en Brasil como "bacupari" ha sido tradicionalmente usada para varios tipos de enfermedades inflamatorias y la evaluación de su composición química, principalmente de las hojas, ha resultado en biflavonoides como compuestos mayoritarios. Estos compuestos fenólicos han demostrado actividad anti-inflamatória validando el uso popular de la planta. En este trabajo se asilaron a partir de tallos secos de la Garcinia gardneriana los biflavonoides: moreloflavona, que consiste en una naringenina unida covalentemente a luteolina, Gb-2a que es un compuesto que consiste en una naringenina unida a un eriodictyol y Gb-2a-7-O-glucose. Estos compuestos ya han sido previamente evaluados en diversas actividades como anti inflamatorios y anti antioxidantes pero no se tiene reporte de su actividad como inhibidores enzimáticos. Sin embargo, los monomeros que los conforman han sido evaluados en la inhibición de la aromatasa y con resultados positivos como en la actividad antidepresiva, para la cual comúnmente son usados los inibidores de MAO-A. En el proceso de aislamiento también fueron encontrados compuestos terpenoides como lupeol y friedelina. Los biflavonoides aislados y purificados se usaron para evaluar la inhibición enzimática “in vitro” en monoaminooxidasas (MAO-A, MAO-B) y aromatasa. Los compuestos presentaron una respuesta positiva calculada con IC50 de hasta 5,47 μM y 1,35 μM para la inhibición de las enzimas MAO-A y aromatasa respectivamente, abriendo el camino a una nueva propuesta de relacionar estas dos enzimas para tratamiento de cánceres hormonodependientes y transtornos de ansiedad y depresión.

Introduction: Osteoporosis belongs to multifactorial metabolic skeletal disease. The breast carcinoma is one of the most common malignities in women worldwide (with an exception of skin tumours). Postmenopausal women with non-metastatic breast carcinoma, which are treated with aromatase inhibitors (AI), have increased risk of developing osteoporosis. In these patients, it is necessary to identify the factors contributing to onset of osteoporosis which can be influenced, and take protective measures towards bone metabolism, in order to reduce the occurrence of serious low-traumatic fractures. Objective: The objective of this thesis is to evaluate the diet with regard to risk factors leading to osteoporosis and bone fractures in postmenopausal women with breast carcinoma without metastases, which are treated with AI. Another objective for this group of women is to evaluate the changes of bone mineral density (BMD) and certain parameters of body composition during long-term treatment of AI. Methods: The present study is based on a questionnaire containing a table to quote a three day diet, which was subsequently analysed to identify the overall energetic income, the income of proteins, fat, carbohydrates, dietary fibre and calcium. The supply of vitamin D was deduced for the serum concentration of...

Rapid increases in plasma androgens are generally associated with short-term aggressive challenges in many breeding vertebrates. However, some animals such as song sparrows (Melospiza melodia) are aggressive year-round, even during the non-breeding season, when gonads are regressed and systemic testosterone (T) levels are non-detectable. In contrast, levels of the prohormone dehydroepiandrosterone (DHEA) are elevated year-round in the plasma and brain. The local conversion of brain DHEA to potent androgens may be critical in regulating non-breeding aggression. 3β-hydroxysteroid dehydrogenase/Δ4-Δ5 isomerase (3β-HSD) catalyzes DHEA conversion to androstenedione (AE) and the cofactor NAD⁺ assists in this transformation. In this thesis, I asked whether brain 3β-HSD activity is regulated by social encounters in seasonally breeding male songbirds. In Experiment 1, I looked at the long-term seasonal regulation of brain 3β-HSD activity. 3β-HSD activity was highest in the non-breeding season compared to the breeding season and molt. In Experiment 2, I hypothesized that brain 3β-HSD activity is rapidly regulated by short-term social encounters during the non-breeding season. A 30 min social challenge increased aggressive behavior. Without exogenous NAD⁺, there was ~355% increase in 3β-HSD activity in the caudal telencephalon and ~615% increase in the medial central telencephalon compared to controls (p<0.05). With exogenous NAD⁺, there was no effect of social challenge on 3β-HSD activity. These data suggest that endogenous cofactors play a critical role in the neuroendocrine response to social challenges. The increase in brain DHEA conversion to AE during social challenges may be a mechanism to rapidly increase local androgens in the non-breeding season, when there are many costs of systemic T. / Science, Faculty of / Zoology, Department of / Graduate

In the teleost brain, radial glial cells (RGCs) are the main macroglia and are stem- like progenitors that express key steroidogenic enzymes, including the estrogen- synthesizing enzyme, aromatase B (cyp19a1b). As a result, RGCs are integral to neurogenesis and neurosteroidogenesis in the brain, however little is known about the permissive factors and signaling mechanisms that control these functions. The aim of this thesis is to investigate if the secretogranin-derived neuropeptide secretoneurin (SN) can exert regulatory control over goldfish (Carassius auratus) RGCs. Immunohistochemistry revealed a close neuroanatomical relationship between RGCs and soma of SNa- immunoreactive magnocellular and parvocellular neurons in the preoptic nucleus in both goldfish and zebrafish (Danio rerio) models. Both intracerebroventricular injections of SNa into the third brain ventricle and SNa exposures of cultured goldfish RGCs in vitro show that SNa can reduce cyp19a1b expression, thus implicating SNa in the control of neuroestrogen production. RNA-sequencing was used to characterize the in vitro transcriptomic responses elicited by 1000 nM SNa in RGCs. These data revealed that gene networks related to central nervous system function (neurogenesis, glial cell development, synaptic plasticity) and immune function (immune system activation, leukocyte function, macrophage response) were increased by SNa. A dose-response study using quantitative proteomics indicates a low 10 nM dose of SNa increased expression of proteins involved in cell growth, proliferation, and migration whereas higher doses down- regulated proteins involved in these processes, indicating SNa has dose-dependent regulatory effects. Together, through these altered gene and protein networks, this thesis proposes SNa exerts trophic and immunogenic effects in RGCs. These datasets identified a total of 12,180 and 1,363 unique transcripts and proteins, respectively, and demonstrated that RGCs express a diverse receptor and signaling molecule profile. Therefore, RGCs can respond to and synthesize an array of hormones, peptides, cytokines, and growth factors, revealing a multiplicity of new functions critical to neuronal-glial interactions.

The medial amygdala (MeA) is a central node in the interwoven circuits that regulate social behavior based on pheromones. Aromatase-expressing (arom+) neurons in the MeA are key for the establishment and maintenance of sex differences. Here, we characterized the intrinsic electrophysiological properties of arom+ neurons and non-aromatase (arom-) neurons in the MeA of male and female mice. Most electrophysiological properties were similar for arom+ neurons in the MeA between sexes, but the relative refractory period was twice as large in female mice. We also show that the firing pattern and firing frequency is markedly different between arom+ and arom- neurons. The activity of MeA neurons could be modulated by estradiol, which reduced activity in arom+ neurons in males. The differences between arom+ and arom- neurons were observed in both sexes suggesting that aromatase expression delineates a neural population in the MeA with similar and unique electrophysiological properties.

Indiana University-Purdue University Indianapolis (IUPUI) / Oral endocrine therapy (OET) is standard therapy for millions of estrogen receptor-positive breast cancer survivors (ER+BCS). OET reduces recurrence, mortality, and metastasis. ER+BCS often do not take their OET as recommended due to adverse side effects. The purpose of this dissertation was to develop an explanatory framework of decision making by women with ER+ breast cancer who report experiencing side effects from OET. This project was comprised of two components. The first component was a systematic review with three main findings: (1) side effects negatively impact OET non-adherence, (2) there is an absence of decisional supports provided to or available for ER+BCS who are experiencing OET side effects,, and (3) ER+BCS likely have unmet decisional needs related to OET. The second component was a grounded theory study that included 31 ER+BCS reporting OET side effects. During a single semi-structured interview, participants described the experience of OET over time. This study produced two qualitatively derived projects. First, a theoretical framework was developed that depicted four stages through which the experience of OET decision making unfolded. The stages were (1) being told what I need to do to live, (2) doing what I need to do to live, (3) enduring what I need to do to live, and (4) deciding how I want to live. Second, a typology was developed that depicted six sources of external decisional supports (healthcare providers, husbands, other breast cancer survivors, friends and family, the internet and other media sources, and God) that met four types of decisional needs (information about OET and its side effects, in-depth discussions about side effects, help in managing side effects, and emotional support). Findings can be used to develop interventions, such as decision aids, to promote quality decision making in women experiencing OET side effects.

No description available.

Prostate cancer is the second most commonly occurring cancer in men in the United States. Generally, an extended period of time is needed for a mutation to develop into a full scale tumor. Because of this long latency period, lifestyle and environmental factors, such as diet, may play an important role in the development and progression of the disease. Diet is one factor that has been implicated in the risk for developing prostate cancer. We previously showed that diets high in soy isoflavones and selenium (Se) decreased androgen receptor expression and expression of androgen regulated genes in healthy rat prostates. The purpose of this study was to determine whether treatment of soy isoflavones and/or supplemental Se provide chemopreventive effects in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model of prostate cancer, and whether the timing of the introduction of these nutrients determines protective effects. Male hemizygous C57/BL6 x FVB TRAMP mice were exposed to a diet high in isoflavones, a 4 mg/kg daily bolus of supplemental Se as methylselenocysteine (MSC), or the combination of high isoflavones and MSC starting at one of two time points: conception or 6 weeks of age, and were killed and dissected for prostate tissue, liver, and serum at either 4 weeks or 12 weeks of age (n per dietary treatment = 20: total mice = 240). Treatment with MSC resulted in decreased urogenital tract weight at 4 and 12 weeks. Treatment with MSC and isoflavones, both individually and as a combination, resulted in decreased androgen receptor expression, 5 alpha-reductase levels, and aromatase levels. The combination of MSC and a basal diet high in isoflavones resulted in decreased serum IGF-1 levels in 12 week TRAMP mice. Treatment from conception resulted in greater decreases in urogenital tract weight, 5 alpha-reductase expression, and aromatase expression than treatment from 6 weeks. This study demonstrated that in 12 week TRAMP mice, reductions in risk factors for prostate cancer by treatments of high isoflavones and supplemental Se are maximized by introduction to treatments at conception.

The accessory olfactory bulb (AOB) processes pheromonal signals which in turn drive social behaviors. Here we identify a tract of aromatase-expressing (arom+) fibers in the dorsal lateral olfactory tract (dLOT) which terminate in the granule cell layer (GCL) of the AOB. We utilized a retrograde tracer in aromatase reporter animals to delineate the source of these fibers. We show that these input fibers emerge almost exclusively from a contiguous population of arom+ neurons that spans the bed nucleus of the accessory olfactory tract (BAOT) and posterioventral subnucleus of the medial amygdala (MeApv). This population of neurons expresses the estrogen receptor alpha and contains more aromatase neurons in male mice than female mice. Thus, this population of feedback neurons can detect neuroendocrine changes and modulate the output of AOB projection neurons in a way that is sexually dimorphic and could influence every downstream target of the AOB.

No description available.