<p>Stem cells have the capacity for both self renewal, and to form all cell types in the body. Interestingly, so called neural stem cells (NSCs) are found in the adult human brain, which is of significance both out of a developmental perspective and from a clinical point of view. At the present moment, the regulation of neural stem cell (NSC) proliferation and fate determination is not completely understood.</p><p>The overall aim of this thesis was to study the mechanisms that regulate NSC proliferation and fate determination <i>in vitro</i> and <i>in vivo</i>. In particular, the roles of the female sex hormone estrogen and the testosterone analogue nandrolone, as well as the melanocortin α-melanocyte stimulating hormone (α-MSH), were analyzed in this context. Also, the breast cancer susceptibility gene one (BRCA-1), was studied in the brain with emphasis on regions containing NSCs.</p><p>Our findings show that estrogen and nandrolone have similar effects on NSCs; both decreased NSC proliferation and increased neurogenesis. Estrogen's ability to reduce proliferation was due to increased levels of p21, an inhibitor of cyclin dependent kinases. In contrast, no change in p21 was observed in the case of nandrolone, indicating differential regulation. Adult rats subjected to nandrolone injections had 30% reduced NSC proliferation in the dentate gyrus, indicating profound effects on NSCs <i>in vivo</i>.</p><p>The melanocortin α-MSH acted as a mitogen by increasing levels of cyclinD1 and retinoblastoma protein; as a result NSC proliferation was doubled.</p><p>Finally, BRCA-1 is expressed while NSCs proliferate, but is drastically down regulated upon differentiation, indicating that BRCA-1 could be used as a possible NSC marker.</p><p>In summary, in this thesis estrogen and nandrolone were identified as NSC regulators which decrease proliferation and positively influence neurogenesis. Also, we have identified the hormone α-MSH as a NSC mitogen, and BRCA-1 as a possible NSC marker.</p>

Stem cells have the capacity for both self renewal, and to form all cell types in the body. Interestingly, so called neural stem cells (NSCs) are found in the adult human brain, which is of significance both out of a developmental perspective and from a clinical point of view. At the present moment, the regulation of neural stem cell (NSC) proliferation and fate determination is not completely understood. The overall aim of this thesis was to study the mechanisms that regulate NSC proliferation and fate determination in vitro and in vivo. In particular, the roles of the female sex hormone estrogen and the testosterone analogue nandrolone, as well as the melanocortin α-melanocyte stimulating hormone (α-MSH), were analyzed in this context. Also, the breast cancer susceptibility gene one (BRCA-1), was studied in the brain with emphasis on regions containing NSCs. Our findings show that estrogen and nandrolone have similar effects on NSCs; both decreased NSC proliferation and increased neurogenesis. Estrogen's ability to reduce proliferation was due to increased levels of p21, an inhibitor of cyclin dependent kinases. In contrast, no change in p21 was observed in the case of nandrolone, indicating differential regulation. Adult rats subjected to nandrolone injections had 30% reduced NSC proliferation in the dentate gyrus, indicating profound effects on NSCs in vivo. The melanocortin α-MSH acted as a mitogen by increasing levels of cyclinD1 and retinoblastoma protein; as a result NSC proliferation was doubled. Finally, BRCA-1 is expressed while NSCs proliferate, but is drastically down regulated upon differentiation, indicating that BRCA-1 could be used as a possible NSC marker. In summary, in this thesis estrogen and nandrolone were identified as NSC regulators which decrease proliferation and positively influence neurogenesis. Also, we have identified the hormone α-MSH as a NSC mitogen, and BRCA-1 as a possible NSC marker.

Supratherapeutic doses of anabolic androgenic steroids (AASs) are administered, not only as performance-enhancing drugs in the world of sports, but also in order to modify behaviour. AAS abusers are at risk of developing serious physical and psychological side effects such as dependence and aggressive behaviour. The aim of this thesis was to investigate the impact of supratherapeutic doses of nandrolone decanoate after subchronic administration on dopamine and serotonin pathways involved in drug dependence and aggression, in the male rat brain. Adult male Sprague-Dawley rats received intramuscular injections of nandrolone decanoate (3 or 15 mg/kg) or vehicle once daily for 14 days. Nandrolone decanoate pre-exposure abolished the effect of amphetamine on the 3,4-dihydroxyphenylacetic acid (DOPAC) tissue level in the hypothalamus and on the DOPAC/dopamine ratio in the hypothalamus and the hippocampus. A significant decrease of the basal extracellular DOPAC and homovanillic acid (HVA) levels could be detected in the nucleus accumbens, which remained low during the first hour following the amphetamine challenge. Nandrolone decanoate significantly reduced the activity of both monoamine oxidase A and B (MAO-A and -B) in the caudate putamen and amygdala. The gene transcript levels of MAO-B, and the dopamine D1 and D4 receptors were altered in limbic regions. No changes in transcriptional levels could be detected among the serotonin receptor genes examined. However, the density of the serotonin transporter protein was elevated in a range of aggression-related brain regions. Taken together, subchronic administration of nandrolone decanoate causes dopaminergic and serotonergic dysregulations in distinct brain regions. These areas of the brain are involved in the development of drug dependence and expression of impulsive and aggressive behaviours. These results may contribute to explain some of the behavioural changes often reported in AAS abusers, such as polydrug use and impaired impulse control.

This is a study about gym training young men (age 18-20) and their attitude against anabolic androgenic steroids, AAS. In our study we examine if the muscular ideal in our society have any effect on young men and the young men’s attitude against their body and their training. We want to find out what attitude gym training young men have against AAS, and also what has had the influence to this attitude.          The study contains six qualitative performed interviews with young men who are training at the gym, which are based on relevant information about their training habits, nutritional supplement, influence, the muscular ideal, the gym culture and medias effect on young men when it comes to body ideals.            The young men’s attitudes is connected and compared to prior research about gym-training young men and what affects them to have a certain attitude against AAS, body and training. In our study we also use a theory by Giddens about social interaction and the late modern society we live in.           The conclusions of the result and analysis is that young men who trains at the gym for the purpose of getting bigger and in relation to the training takes nutritional supplements, have a more liberal attitude against AAS compared to those young men who doesn’t. Media, friends, equals at the gym and the gym culture are all factors that affect young men in their positive attitude in opposition to AAS.

Denna kvalitativa studie handlar om några behandlares upplevelser och erfarenheter kring vilka personer som hamnar i missbruk av anabola androgena steroider(AAS). Den belyser även vilken behanding som finns för problematiken. För att erhålla empiri används semistrukturerade intervjuer på fyra personer som arbetar med behandling av AAS. Resultatet visar att man kan kategorisera AAS-användare i tre olika grupper. När klienter kommer till behandling är det viktigt att man ser till helhetsbilden och att man ser varje individ för sig. Metoder som finns är terapi för det sjuka kroppsidealet, hjälp med träningsmissbruket, läkemedelsassisterad behandling samt annan psykosocial terapi. En intressant slutsats är att det finns hjälp att få vid AAS-missbruk, men tyvärr finns det inte resurser att hjälpa alla. Det finns fortfarande mycket kvar att lära inom ämnet och man behöver forska kring fler och bättre behandlingsmetoder som kan passa vid detta missbruk.

Syftet med föreliggande uppsats är att undersöka hur patienter och behandlare ser på vad som leder till ett bruk alternativt missbruk av anabola androgena steroider, AAS. Uppsatsen har en kvalitativ, fenomenografisk ansats. Ostrukturerade intervjuer genomfördes med fem patienter och tre behandlare vid Beroendecentrum i Örebro. Materialet analyserades med hjälp av tematisk analys. Sju teman utkristalliserade sig som resultat; Samhälle, Uppväxt, Socialt umgänge, Psykologiska sårbarheter, Attityder, Kroppsbild och Övrigt. Det omfattande resultatet kan anses visa på en komplexitet i förklaringen till vad som leder till att en individ börjar bruka eller missbruka AAS. / This study aims to examine how patients and clinicians look at what leads to the use or abuse of anabolic androgenic steroids, AAS. The study uses a qualitative phenomenographic method. The research data was collected with unstructured interviews with five patients and three clinicians at Beroendecentrum in Örebro. The research data was analyzed through the use of a thematic analysis. The results were the seven themes that emerged; Society, Childhood, Social relations, Psychological vulnerabilities, Attitudes, Body image and Other. The extensive results can be looked upon as showing the complexity in the explanation of what leads to an individuals use or abuse of AAS.

<p>This is a study about gym training young men (age 18-20) and their attitude against anabolic androgenic steroids, AAS. In our study we examine if the muscular ideal in our society have any effect on young men and the young men’s attitude against their body and their training. We want to find out what attitude gym training young men have against AAS, and also what has had the influence to this attitude.</p><p>         The study contains six qualitative performed interviews with young men who are training at the gym, which are based on relevant information about their training habits, nutritional supplement, influence, the muscular ideal, the gym culture and medias effect on young men when it comes to body ideals.  </p><p>         The young men’s attitudes is connected and compared to prior research about gym-training young men and what affects them to have a certain attitude against AAS, body and training. In our study we also use a theory by Giddens about social interaction and the late modern society we live in. </p><p>         The conclusions of the result and analysis is that young men who trains at the gym for the purpose of getting bigger and in relation to the training takes nutritional supplements, have a more liberal attitude against AAS compared to those young men who doesn’t. Media, friends, equals at the gym and the gym culture are all factors that affect young men in their positive attitude in opposition to AAS.</p>

Made available in DSpace on 2014-06-11T19:23:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-01-29Bitstream added on 2014-06-13T20:29:45Z : No. of bitstreams: 1 carmo_ca_me_botib.pdf: 354246 bytes, checksum: 4c9e96974ccabd93669458a1fdf56b19 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Os anabolizantes esteróides têm sido amplamente utilizados por profissionais e atletas de elite para melhorar sua aparência e habilidades atléticas. Além disso, eles apresentam um importante papel quimioterapêutico no tratamento de vários tipos de distúrbios metabólicos, homeostáticos e sexuais, em ambos os sexos. Tendo em vista que muitas drogas esteróides têm apresentado diferentes resultados considerando efeitos genotóxicos e mutagênicos, o objetivo desse trabalho foi avaliar o potencial genotóxico do hormônio nandrolona (deca-durabolin®) in vivo em células da medula óssea e do sangue periférico de camundongos, usando o teste do micronúcleo e o ensaio do cometa, respectivamente. Os animas receberam injeção intradérmica de 3 concentrações do hormônio esteróide (1.0, 2.5 e 5.0 mg/kg peso corporal). As células foram coletadas 24 h após o tratamento hormonal para o teste do micronúcleo (avaliação da clastogenicidade) e o teste do cometa (avaliação da genotoxicidade). O teste do micronúcleo evidenciou que as duas maiores doses testadas da nandrolona induziram aumentos estatisticamente significativos de células micronucleadas e o teste do cometa não evidenciou aumento significativo de danos no DNA nos linfócitos do sangue periférico. Sob estas condições experimentais, conclui-se que o hormônio esteróide nandrolona apresentou efeito clastogênico e/ou aneugênico e, por outro lado, não foram observados efeitos genotóxicos quando o mesmo foi administrado intradermicamente em camundongos / Anabolic androgenic steroids have been widely used by professional and elite athletes to improve their appearance and athletic abilities. Besides, they have an important place in the chemotherapeutic treatment of various types of metabolic, homeostatic, and sexual disorders in both sexes. Since many steroidal drugs have been found to be different results considering genotoxic and mutagenic effects, the aim of this study was to evaluate the genotoxic potential of nandrolone (deca-durabolin®) in vivo in bone marrow and peripheral blood cells of mice, using micronucleus and comet assays, respectively. The animals received intradermal injection of the 3 concentrations of the steroid (1.0, 2.5 and 5.0 mg/kg body weight). The cells were collected 24 h after the hormone-treatment for the micronucleus (clastogenicity endpoint) and comet assays (genotoxicity endpoint). Micronucleus test showed that the two higher tested-doses of the nandrolone induced statistically significant increase of the micronucleated cells and comet assay no evidenced significant increase in the DNA damage of the lymphocytes from peripheral blood. Under our experimental conditions, the nandrolone steroid hormone showed clastogenic and/or aneugenic effects and, on the other hand, no genotoxic effects when administered intradermally to mice

Submitted by Erika Demachki (erikademachki@gmail.com) on 2017-01-02T16:23:41Z No. of bitstreams: 2 Dissertação - Janaína Ribeiro Costa - 2016.pdf: 3702249 bytes, checksum: c5c72df64f423c647fbe09f7ed58d147 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Erika Demachki (erikademachki@gmail.com) on 2017-01-02T16:40:21Z (GMT) No. of bitstreams: 2 Dissertação - Janaína Ribeiro Costa - 2016.pdf: 3702249 bytes, checksum: c5c72df64f423c647fbe09f7ed58d147 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-01-02T16:40:21Z (GMT). No. of bitstreams: 2 Dissertação - Janaína Ribeiro Costa - 2016.pdf: 3702249 bytes, checksum: c5c72df64f423c647fbe09f7ed58d147 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-10-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The prostate is an accessory gland of the mammalian reproductive system with important role in reproduction. The prostatic tissue is regulated by hormones with its homeostasis dependent on a balanced hormonal interaction. The exposure to environmental chemicals with hormonal activities can cause disorders in the prostate increasing the probability of this gland to develop major lesions. Hormonally active chemicals are present in the environment in substantial amounts and forms. Amongst them are the parabens, a class of preservatives with antifungal and antimicrobial activities commonly used in the cosmetic, pharmaceutical and food industry. They are known for affecting the reproductive system and act as endocrine disruptors that mimics the physiological effects of estrogens. Up their, it is unclear whether the exposure to parabens alters the prostate morphophysiology. Therefore, it is relevant to comprehend whether the methylparaben can lead to the development of lesions in the prostate in adult gerbils. Thus, the aim of this work was to evaluate the prostate of adult gerbils exposed to methylparaben. For this, males and females aging 90 days received, through gavage, 500 mg/kg of methylparaben diluted in 1% hydroxyethyl cellulose. These animals were divided into three subgroups that were euthanized after 3 (3P), 7 (7P) and 21 days of treatment (21P). The prostates were collected for structural, cytochemical and immunohistochemical analysis. The results demonstrated that the exposure to methylparaben reduced the body weight of males of 3P and 7P groups, and testis weight of 7P and 21P groups. In the females we observed an increase in the prostatic complex weight of the 21P group. In both sexes, Gömöri’s reticulin staining showed a remodeling of the stromal compartment with reticular fibers disorganization and collagen fibers increase. Besides, males and females presented important morphological alterations as hyperplasic growth foci. In females, it was observed the presence of prostatic intraepithelial neoplasia, stromal inflammatory foci and an increase of ERα-positive cells. Immunohistochemical data showed an increase of ARpositive cells and in the proliferation rates for both genders. Altogether, these data demonstrate that methylparaben was capable to interfere in androgenic and estrogenic receptors, suggesting that this chemical might have estrogenic and anti-androgenic activity in the prostate. In males there was an intense immunostaining for MGMT in all treated groups whereas in females only in the 3P group. The immunostaining for MGMT in the prostate of males and females suggests that the exposure to methylparaben made the gland more susceptible to epigenetic modifications. The results obtained with this study are alarming, as they indicate that the increasing consumption of parabens by urban population can be related with the arising of morphophysiological alterations in prostate. / A próstata é uma glândula acessória do aparelho reprodutor dos mamíferos e tem importante função na reprodução. O tecido prostático é regulado por hormônios esteroides, sendo que sua homeostase depende de uma interação hormonal equilibrada. A exposição a químicos ambientais que apresentam atividade hormonal pode ocasionar distúrbios na próstata, aumentando a probabilidade dessa glândula desenvolver lesões. Compostos químicos hormonalmente ativos estão presentes em grande quantidade e de diversas formas no meio ambiente. Dentre estas substâncias estão os parabenos, uma classe de conservantes com ação antimicrobiana e antifúngica amplamente utilizada na indústria cosmética, farmacêutica e alimentícia. Os parabenos são conhecidos por perturbar o sistema reprodutivo e agir como desreguladores endócrinos que mimetizam os efeitos fisiológicos dos estrógenos. Até o momento, não está claro se os parabenos podem alterar a morfofisiologia da próstata. Portanto, é relevante entender se o metilparabeno pode predispor a próstata a desenvolver lesões na idade adulta. Assim, o objetivo desse trabalho foi avaliar a próstata de gerbilos adultos expostos ao metilparabeno. Para isto, machos e fêmeas com 90 dias de idade receberam, por gavagem, 500 mg/kg de metilparabeno diluídos em hidroxietil-celulose a 1%. Estes animais foram divididos em três subgrupos que foram sacrificados após 3, 7 e 21 dias de tratamento. As próstatas foram coletadas para análises estruturais, citoquímicas e imunohistoquímicas. Os resultados monstraram que a exposição ao metilparabeno diminuiu o peso dos testículos dos grupos 7 e 21 dias. Nas fêmeas houve aumento do peso do complexo prostático do grupo de 21 dias. Em ambos os sexos, a Reticulina de Gömöri mostrou um remodelamento do compartimento estromal com desorganização das fibras reticulares e aumento das fibras colágenas. Além disso, machos e fêmeas apresentaram alterações morfológicas importantes como focos de crescimento hiperplásico do epitélio secretor. Nas fêmeas observou-se a presença de neoplasia intraepitelial prostática, focos inflamatórios estromais, e aumento de células ERα- positivas. Houve um aumento do número de células AR-positivas, e aumento das taxas de proliferação celular em ambos os sexos. Em conjunto, estes dados indicam que o metilparabeno foi capaz de interferir com receptores androgênicos e estrogênicos, sugerindo que este químico pode ter atividade estrogênica e antiandrogênica na próstata. Nos machos houve uma intensa imunomarcação para MGMT (O6-Metilguanina-DNAMetiltransferase) em todos os grupos tratados e nas fêmeas apenas no grupo 3P. A imunomarcação para MGMT na próstata masculina e feminina sugere que a exposição ao metilparabeno tornou a glândula mais suscetível a modificações epigenéticas. Os resultados obtidos com este estudo são relevantes, pois demonstram que o consumo crescente de parabenos pelas populações humanas pode estar relacionado com o surgimento de alterações morfofisiológicas da próstata.

Diante da hipótese de que micropartículas poliméricas podem atravessar a barreira epidérmica através da rota transfolicular, e baseado na evidência de que a iontoforese é um método que consegue direcionar a liberação de fármacos para os folículos pilosos, este trabalho teve como objetivo estudar in vitro a permeação cutânea do minoxidil sulfato (MXS), fármaco utilizado no tratamento da alopecia androgênica, tanto em sua forma microencapsulada como não encapsulada utilizando ou não a iontoforese, na tentativa de aumentar, controlar e direcionar a sua liberação tópica para o folículo piloso. O MXS foi primeiramente incorporado em um gel hidrofílico contendo 2,0% (m/m) do ativo e sua permeação e retenção cutânea in vitro verificada com e sem a presença de corrente elétrica durante 6 h, utilizando células de difusão e pele de orelha de porco. A quantidade de MXS retida no EC da pele foi determinada e diferenciada daquela retida nos folículos pilosos utilizando-se a técnica denominada tape stripping diferencial. Foi observado que o fluxo passivo de fármaco através da pele aumentou 150 vezes com aplicação de iontoforese anódica e que o aumento do pH da formulação de 3,5 para 5,5 restringiu 3 vezes essa permeação iontoforética e aumentou a retenção do MXS no EC e folículos pilosos. Estes resultados mostram que a iontoforese do MXS nestas condições é capaz de promover a liberação folicular do fármaco de maneira bastante significativa. Uma série de micropartículas de quitosana contendo MXS foi obtida por spray drying modificando quantidades e proporções de polímero e fármaco. O sistema selecionado para estudo foi obtido a partir de 1,50 g de polímero e 0,75 g de MXS, e apresentou alta eficiência de encapsulação (~82%), diâmetro médio igual a 3,05 µm, morfologia esférica e sem porosidades, e potencial zeta igual a + 5,87 mV. Quando incorporadas a uma formulação hidroalcoólica, essas micropartículas sofreram intumescimento, aumentando 1,5 vezes o seu diâmetro médio, mas não tiveram sua morfologia esférica alterada. Experimentos de liberação in vitro mostraram que as micropartículas obtidas foram capazes de sustentar 3,5 vezes a liberação do MXS. As micropartículas ainda restringiram a permeação passiva do fármaco, reduzindo 2 vezes seu fluxo de permeação e aumentando em 5 vezes a retenção de fármaco na região folicular, apesar das partículas em si não penetrarem a pele após administração passiva. Assim, este sistema foi capaz de promover uma liberação mais sustentada do fármaco, o que deve reduzir o número de aplicações do produto pelo paciente ao longo do dia, e garantiu a entrada de grandes quantidades do fármaco nos folículos pilosos, seu alvo de ação. A iontoforese dessas micropartículas, apesar de também não fazê-las penetrar a pele, conseguiu direcioná-las mais rapidamente para as aberturas foliculares, como mostrou os estudos de microscopia confocal de varredura a laser das micropartículas marcadas. Adicionalmente, a iontoforese aumentou 6 vezes a quantidade de MXS retida nos folículos já nas primeiras 3 h de aplicação, garantindo assim que grandes quantidades do fármaco atingissem seu local de ação mais rapidamente que quando as partículas foram aplicadas passivamente sobre a pele. / Given the hypothesis that polymeric microparticles can penetrate the skin barrier along the transfollicular route, and based on the evidence that iontophoresis is a method that can direct the delivery of drugs to the hair follicles, this work aimed to study the in vitro skin permeation of minoxidil sulfate (MXS), a drug used to treat androgenic alopecia, both in its micro-encapsulated and non-encapsulated form, using or not iontophoresis, in an attempt to increase, control and direct its topical delivery to the hair follicle. The MXS was first incorporated in a hydrophilic gel containing 2.0% (w/w) MXS and its skin permeation and retention was in vitro observed with and without the presence of electric current for 6 h, using diffusion cells and skin of porcine\'s ears. The amount of MXS retained in EC was determined and differentiated from that retained in the hair follicles using the technique called differential tape stripping. It was observed that the passive flux of drug through the skin was increased 150-fold with the application of anodal iontophoresis and, by increasing the pH of the formulation from 3.5 to 5.5, iontophoretic permeation of MXS was 3-fold restricted, whereas it increased its retention in stratum corneum and hair follicles. These results show that iontophoresis of MXS in these conditions can promote the follicular delivery of the drug quite significantly. A series of chitosan microparticles containing MXS was obtained by spray drying, modifying quantities and proportions of polymer and drug. The system selected for study was obtained from 1.50 g of polymer and 0.75 g of MXS, and showed high encapsulation efficiency (~ 82%), mean diameter of 3.05 µm, spherical morphology without porosities, and zeta potential equal to + 5.87 mV. When incorporated into a hydro ethanolic formulation, these microparticles suffered swelling, increasing 1.5 times its diameter, but their spherical morphology was not modified. Permeation experiments showed in vitro that the microparticles obtained were able to sustain 3.5 times the release of MXS. The microparticles also restricted the passive permeation of the drug, reducing 2-fold its permeation flux and increasing by 5-fold the retention of drug in the follicular region, although the microparticles themselves did not penetrate the skin after passive administration. Thus, this system was able to promote a more sustained release of the drug, which must reduce the number of product applications by the patient throughout the day, and ensured the entry of large amounts of drug in hair follicles, their target. Iontophoresis of microparticles, although not making them penetrate the skin either, was able to direct them quickly to the follicular openings, as shown by laser confocal scanning microscopy studies of the labeled microparticles. In addition, iontophoresis increased 6-fold the amount of MXS retained in the follicles within the first 3 h of application, thereby ensuring that large quantities of the drug achieved its site of action more quickly than when the particles were applied passively to the skin.