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Bernard, Valérie. "Rôle de la prolactine dans la tumorigenèse du prolactinome." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS280.
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Nous avons souhaité, dans ce travail de Thèse, préciser le rôle de l’hormone prolactine (PRL) dans la tumorigenèse des prolactinomes. Nous avons tout d’abord décrit l’histoire naturelle et moléculaire des tumeurs lactotropes développées par le modèle de souris Prlr-/-, invalidé de façon globale pour le récepteur de la PRL (PRLR). Les femelles Prlr-/- développent des prolactinomes avec 100% de pénétrance à 12 mois. Ces tumeurs sont très sécrétantes, invasives et prolifératives. L’analyse transcriptomique comparative des hypophyses de souris Prlr+/+ et Prlr-/- nous a permis de mettre en évidence de nouvelles voies de signalisation impliquées dans la survenue de ces tumeurs. Ces nouveaux gènes candidats seront à rechercher chez l’Homme. Par ailleurs, l’étude d’un autre modèle murin développé dans le cadre de ce travail, invalidé de façon spécifique dans la cellule lactotrope, a permis de démontrer pour la première fois in vivo que la PRL exerçait un rétrocontrôle autocrine sur la sécrétion et la prolifération des cellules lactotropes. Bien que nous n’ayons pas retrouvé de mutation germinale du PRLR dans une large cohorte de patients atteints de prolactinome sporadique, nos résultats suggèrent que des mutations somatiques de ce gène ne sont pas à exclure et pourraient contribuer à la survenue de la pathologie humaineIn this work, we investigated the role of prolactin (PRL) in prolactinoma tumorigenesis. We first described the natural and molecular history of lactotroph cell tumors developed by the Prlr-/- mouse model, globally invalidated for the PRL receptor (PRLR). The Prlr-/- females develop prolactinomas with 100% penetrance at 12 months of age. These tumors are highly secreting, invasive and proliferative. The comparative transcriptomic analysis of pituitaries from Prlr+/+ and Prlr-/- mice suggested new signaling pathways involved in lactotroph adenoma developement in this mouse model. The role of these novel candidate genes remains to be demonstated in Humans. Furthermore, by studying another mouse model developed during this work, deleted for Prlr only in lactotroph cells, we demonstrated for the first time that PRL exerts an autocrine feedback on lactotroph cell secretion and proliferation in vivo. Although we did not find any germline mutation of PRLR in a large cohort of patients with sporadic prolactinoma, our results suggest that somatic mutations of this gene cannot be excluded and may contribute to the onset of the human pathology
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Gordon, Timothy Jason. "THE BIOLOGICAL, STRUCTURAL AND KINETIC PROPERTIES OF PROLACTIN, PROLACTIN RECEPTOR ANTAGONISTS, GROWTH HORMONE AND THE PROLACTIN RECEPTOR." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366356833.
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Ueda, Eric Kinnosuke Martins. ""Prolactina humana pseudofosforilada (S179D-hPRL) é um potente fator anti-angiogênico in vitro e in vivo"." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-28052007-162443/.
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S179D prolactina (hPRL) é uma mímica molecular da prolactina humana fosforilada. Demonstrou-se que a S179D-hPRL era anti angiogênica nos ensaios de angiogênese baseados na membrana corialantóica de galinha e na córnea de camundongos. Investigações posteriores realizadas empregando modelos in vitro demonstraram que o tratamento com S179D-hPRL diminuiu o número de células viáveis, reduziu a formação de túbulos em Matrigel e interferiu com a migração e invasão da matriz extracelular. A análise dos fatores de crescimento de células endoteliais humanas tratadas com S179D-hPRL revelou: uma diminuição na expressão ou liberação da PRL endógena, da heme-oxigenase-1, do fator de crescimento de fibroblasto básico (bFGF) e um aumento na expressão de dois inibidores teciduais de metaloproteases. A S179D-hPRL também bloqueou a sinalização provocada por bFGF nessas células. Nós concluímos que essa mímica molecular do hormônio pituitário fosforilado é uma potente proteína anti-angiogênica, em parte devido á sua habilidade de reduzir o estímulo autócrino de fatores de crescimento de células endoteliais de cordão umbilical humano (HUVEC), por sua capacidade de bloquear a sinalização promovida pelo bFGF e por sua habilidade de interferir na migração endotelial. Também foi estudada a influência da S179D-hPRL na apoptose em células endoteliais humanas, empregando caspase-8 como um marcador da via extrínseca, e a liberação de citocromo C como um marcador da via intrínseca. As duas cascatas convergem na ativação da caspase-3, que cliva a fator de fragmentação de DNA (DFF45). Uma incubação de três dias com 50 ng/mL de S179D-hPRL quadruplicou o número de células apoptóticas; esse efeito duplicou-se com uma concentração de 100 ng/mL e atingiu um ápice com 500 ng/mL. A clivagem de DFF45 e da pro-caspase-8 foi detectado com 100 ng/mL. Citocromo C, porém, só foi observado com concentrações de 500 ng/mL. O regulador de ciclo celular p21 (um marcador pró-apoptótico) elevou-se com 100 ng/mL, enquanto que um incremento do supressor tumoral p53 necessitou três vezes o tempo de incubação e 500 ng/mL. A atividade do promotor de p21 foi máxima com 50 ng/mL do análogo de hPRL, enquanto que 500 ng/mL foram necessários para se visualizar uma alteração significativa na atividade do promotor de Bax (um indicador da atividade de p53). Como previamente demonstrado na literatura, S179D-hPRL bloqueou a fosforilação da quinase regulada extracelularmente (ERK) em resposta ao bFGF, mas também causou uma ativação tardia e prolongada da ERK. PD 98059 [inibidor específico da proteína quinase ativada por mitógeno (MAPkinase)] inibiu essa ativação tardia e sustentada assim como outros efeitos da S179D-hPRL, exceto aquele sobre a indução de p53 e ativação do promotor de Bax. Podemos concluir que baixas doses de S179D-hPRL bloqueiam a sinalização de ERK induzida por bFGF e concomitantemente ativam a ERK em um tempo diferente, resultando na elevação de p21 e ativando a via extrínseca de apoptose. Maiores tempos de incubação e concentração, entretanto, ativam a via intrínseca empregando uma cascata intracelular diferente. Esses achados sugerem que níveis circulantes de PRL fosforilada podem inibir a progressão do câncer e, portanto, S179D-hPRL poderia ser um agente anti-angiogênico útil na terapêutica.S179D-prolactin (hPRL) is an experimentally useful mimic of naturally phosphorylated human prolactin. S179D-hPRL, but not unmodified PRL, was found to be anti-angiogenic in both the chorioallantoic membrane and corneal assays. Further investigation using human endothelial in vitro models showed reduced cell number, reduced tubule formation in Matrigel, and reduced migration and invasion, as a function of treatment with S179D-hPRL. Analysis of growth factors in human endothelial cells in response to S179D-hPRL showed a decreased expression or release of endogenous PRL, heme-oxygenase-1, basic fibroblast growth factor (bFGF), angiogenin, epidermal growth factor and vascular endothelial growth factor and an increased expression of inhibitors of matrix metalloproteases. S179D-hPRL also blocked signaling from bFGF in these cells. We conclude that this molecular mimic of a pituitary hormone is a potent anti-angiogenic protein, partly as a result of its ability to reduce utilization of several well-established endothelial autocrine growth loops, partly by its ability to block signaling from bFGF and partly because of its ability to decrease endothelial migration. We also examined the influence of S179D-hPRL on apoptosis in human endothelial cells, using procaspase-8 as a marker of the extrinsic pathway, and cytochrome C release as a marker of the intrinsic pathway. Both pathways converge at caspase-3, which cleaves DNA fragmentation factor (DFF45). A 3-day incubation with 50 ng/ml S179D-hPRL quadrupled the early apoptotic cells; this effect was doubled at 100 ng/ml and maximal at 500 ng/ml. DFF45 and pro-caspase 8 cleavage were detectable at 100 ng/ml. Cytochrome C, however, was unaffected until 500 ng/ml. p21 increased at 100 ng/ml, whereas a change in p53 activity required both triple the time and 500 ng/ml. p21 promoter activity was maximal at 50 ng/ml, whereas 500 ng/ml were required to see a significant change in the Bax promoter (a measure of p53 activity). As previously shown, S179D-hPRL blocked extracelular regulated kinase (ERK) phosphorylation in response to bFGF, but, in addition, continued co-incubation showed a delayed and prolonged activation of ERK. PD98059 [a specific mitogen-activated protein kinase (MAPkinase) inhibitor] inhibited this delayed activation of ERK and the effects of S179D-hPRL on all parameters except p53, or activity of the Bax promoter. We conclude that low doses of S179D-hPRL block bFGF-induced ERK signaling and yet activates ERK in a different time frame to elevate p21, and activate the extrinsic pathway. Longer incubations and higher concentrations, however, additionally activate the intrinsic pathway using an alternate intracellular signal. These findings suggest that circulating levels of phosphorylated hPRL may reduce the progression of cancer and, furthermore, that S179D-hPRL may be a useful anti-angiogenic therapeutic.
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Furigo, Isadora Clivatti. "Estudo do mecanismo de ação da bromocriptina e de antagonistas de prolactina no tratamento do Diabetes Mellitus tipo 2 e da obesidade." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-16052017-145647/.
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Atualmente, é crescente o interesse em estudar o potencial do Sistema Nervoso Central (SNC) como alvo de medicamentos antidiabéticos, uma vez que ele possui receptores de insulina e desempenha papel crítico na regulação da homeostase glicêmica. Nesse sentido, o Cycloset® (mesilato de bromocriptina de liberação rápida), um medicamento de ação central aprovado nos Estados Unidos para o tratamento do DMT2, atende a essa tendência atual. Trabalhos prévios mostram efeitos benéficos da bromocriptina (Bromo) sobre a hiperglicemia e hiperlipidemia em modelos de animais obesos tratados com essa droga. Por ser um agonista dopaminérgico, um dos possíveis mecanismos de ação dessa droga pode ser bloqueando a liberação e produção de prolactina (Prl). Níveis elevados de prolactina na circulação sanguínea, observados tanto em indivíduos com prolactinomas como em pessoas tratadas com medicamentos que causam hiperprolactinemia, geram anormalidades no metabolismo de carboidratos e lipídeos, o que pode levar a um quadro de síndrome metabólica. Na presente tese, testamos a hipótese de que ao menos parte dos efeitos antidiabéticos da Bromo seja mediada pela inibição da secreção de prolactina. Avaliamos os efeitos do tratamento com Bromo em camundongos machos e fêmeas geneticamente obesos e resistentes à insulina (ob/ob), bem como testamos se os efeitos benéficos do medicamento seriam revertidos com a reposição de Prl. Machos tratados com Bromo apresentaram maior sensibilidade à insulina, enquanto que a reposição de Prl manteve os animais menos sensíveis, tais como os animais do grupo controle. As fêmeas tratadas com Bromo apresentaram tendência à melhora de sensibilidade à insulina, bem como foram mais tolerantes à glicose, sendo que a reposição de Prl em animais tratados com Bromo também reverteu o efeito benéfico do medicamento. Dessa forma, demonstramos que ao menos parte dos efeitos antidiabéticos da Bromo é mediada pela inibição da secreção basal de Prl. Em um segundo conjunto de experimentos, testamos se a administração de antagonistas de prolactina (G129R-hPrlR) em machos ob/ob, por vias centrais ou periféricas, produziria efeito antidiabético. Observamos que tanto o tratamento periférico como o central diminui a curva glicêmica dos animais em testes de tolerância à glicose e melhoram a sensibilidade à insulina, embora ainda não tenhamos obtido valores significativos devido a nossa amostragem. Por fim, investigamos se a ação da Prl sobre o metabolismo ocorre por meio da interação com o receptor de estrógeno alfa (ERα). Verificamos que receptores de prolactina e de ERα são expressos em áreas comuns no SNC e que variações nos níveis circulantes de estrógeno causam mudanças na sensibilidade à prolactina. Portanto, no presente trabalho, identificamos o possível mecanismo pelo qual a Bromocriptina promove melhorias no controle glicêmico e, de forma inédita, produzimos evidências que o uso de antagonistas de prolactina pode ter potencial no tratamento do DMT2.Type 2 Diabetes mellitus (T2DM) is a syndrome characterized by dysfunctions in the metabolism of glucose, amino acids and free fat acids. Although most of the drugs currently used to treat T2DM targets peripheral organs, a growing interest in studying the Central Nervous System (CNS) as a potential target of antidiabetic drugs is appearing. The CNS possesses insulin receptors and plays a critical role in regulating glucose homeostasis. In this sense, Cycloset® (quick release bromocriptine mesylate) a drug that acts on CNS, was recently approved in United States to treat T2DM. Previous studies have shown beneficial effects of bromocriptine (Bromo) on hyperglycemia and hyperlipidemia in obese animal models. As a dopaminergic agonist, a possible mechanism of action of this drug could be caused by a decreased prolactin (Prl) production and release. High serum prolactin levels, as observed in patients bearing prolactinomas or individuals using drugs that induce hyperprolactinemia, generate abnormalities in carbohydrate and lipid metabolism, which can lead to metabolic syndrome. In the current thesis, we tested the hypothesis that part of bromocriptine antidiabetic effects is due to an inhibition of prolactin secretion. We evaluated Bromo effects in genetically obese and insulin resistant male and female mouse (ob/ob), as well as we tested whether replacing Prl could reverse the beneficial effects of Bromo. Males treated with Bromo showed lower insulin resistence, whereas Prl replacement decreased insulin sensitivity. Females treated with Bromo showed tendency towards an improvement in their insulin sensitivity and glucose tolerance. Prl replacement also reversed the beneficial effects of Bromo in this group. Thus, we demonstrated that at least part of the antidiabetic effects of Bromo is due to inhibition of Prl secretion. In another set of experiments, we tested whether central or peripheral treatment with prolactin antagonists (G129R-hPrlR) causes antidiabetic effects in ob/ob male mice. Both peripheral and central treatment decreased the glycemic curve during glucose and insulin tolerance tests, although we still did not obtain statistically significant values with our sample size. Lastly, we investigated whether metabolic Prl action occurs due to a putative interaction with estrogen receptor alpha (ERα). We found a wide co-expression between Prl receptor and ERα in the CNS. Additionally, changes in estrogen levels decrease prolactin sensitivity. Therefore, in the present study we identified the possible mechanism by which bromocriptine promotes improvements in glycemic control, and for the first time, we obtained evidence that the use of prolactin antagonists can have a potential effect in the treatment of T2DM.
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Amaral, Vinícius Cestari do. "Expressão gênica da prolactina e seus receptores na hipófise e no útero de camundongo fêmea tratado com metoclopramida." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-18092012-114713/.
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INTRODUÇÃO: A prolactina é um hormônio polipeptídico, que possui reconhecida ação sistêmica, principalmente na fisiologia da reprodução, porém, seu desequilíbrio, em especial a hiperprolactinemia, é cada vez mais frequente na prática clínica. Apesar de ser um distúrbio relativamente comum, ainda existem dúvidas quanto aos efeitos moleculares da hiperprolactinemia no trato genital, particularmente no útero, e também na hipófise. O presente estudo teve por objetivo verificar os efeitos da hiperprolactinemia induzida pela metoclopramida na expressão gênica da prolactina e de seus receptores no útero e na hipófise de camundongo fêmea. MÉTODOS: Utilizaram-se 49 camundongos fêmeas (Wistar), randomicamente divididas em 7 grupos contendo 7 animais cada: 1) SS não ovariectomizadas que receberam solução salina (veículo); 2) M não ovariectomizadas tratadas com metoclopramida; 3) OSS ovariectomizadas tratadas com solução salina (veículo); 4) OM ovariectomizadas tratadas com metoclopramida; 5) OME ovariectomizadas tratadas com metoclopramida e 17-estradiol; 6) OMP ovariectomizadas tratadas com metoclopramida e progesterona micronizada; 7) OMEP ovariectomizadas tratadas com metoclopramida, 17-estradiol e progesterona micronizada. Após 50 dias os animais foram sacrificados sendo retirados o útero e a hipófise de cada animal para extração do ácido ribonucleico total, que foi utilizado para a síntese de ácido desoxirribonucleico complementar e avaliação da expressão gênica da prolactina e das diferentes isoformas de seus receptores, por reação em cadeia da polimerase em tempo real. RESULTADOS: Na hipófise, em animais não ovariectomizados, o tratamento com metoclopramida aumentou a expressão do gene que codifica a prolactina em relação ao tratamento apenas com o veículo. Nos animais castrados, a progesterona isoladamente ou associada ao estrogênio determinou o incremento do RNA mensageiro da prolactina em relação aos outros animais castrados que receberam outras combinações de tratamento. Este efeito foi semelhante ao da metoclopramida em animais com os ovários intactos. Em relação ao receptor de prolactina, o estrogênio e a progesterona, isoladamente, foram responsáveis pelo incremento da isoforma S2. No útero houve aumento na expressão de RNA mensageiro de prolactina após tratamento com metoclopramida ou com tratamento isolado ou combinado de estrogênio e progesterona. A ovariectomia determinou a redução da expressão das isoformas S1 e S2 do receptor de prolactina de todas as isoformas estudadas. Já o tratamento estroprogestativo determinou elevação da formas S3 e L do receptor, enquanto com a progesterona isoladamente causou apenas o incremento da forma L do receptor da prolactina no útero dos animais castrados. CONCLUSÕES: Nossos dados sugerem que o tratamento com metoclopramida altera de forma diferente a expressão de prolactina e de seus receptores quando se compara o resultado da hipófise em relação ao útero em camundongos fêmeas castrados e tratados com esteróides sexuaisINTRODUCTION: Prolactin is a polypeptide hormone with a recognized systemic action mainly on reproductive physiology. However, prolactin imbalance, particularly hyperprolactinemia, is increasingly more frequent in clinical practice. Although it is a comparatively common disorder, there are still doubts about the molecular effects of hyperprolactinemia on the genital tract especially in the uterus and the pituitary. The present study aimed at verifying the effects of metoclopramide-induced hyperprolactinemia on the gene expression of prolactin and its receptors in the uterus and pituitary of the female mouse. METHODS: Forty-nine female Wistar mice were randomized to 7 equal-sized groups as follows: 1) SS nonoophorectomized mice treated with saline solution (vehicle); 2) M nonoophorectomized mice treated with metoclopramide; 3) OSS oophorectomized mice treated with saline solution (vehicle); 4) OM oophorectomized mice treated with metoclopramide; 5) OME oophorectomized mice treated with metoclopramide and 17-estradiol; 6) OMP oophorectomized mice treated with metoclopramide and micronized progesterone; 7) OMEP oophorectomized mice treated with metoclopramide, 17-estradiol, and micronized progesterone. The animals were sacrificed 50 days after the end of the treatment, and the uterus and pituitary of each animal were removed for extraction of total ribonucleic acid, which was then used for synthesizing complementary deoxyribonucleic acid and for evaluating the gene expression of prolactin and the different isoforms of its receptors by the real-time polymerase chain reaction. RESULTS: In the pituitary of the nonoophorectomized mice, the treatment with metoclopramide against that with vehicle alone increased the expression of the prolactin-encoding gene. In the castrated animals, progesterone by itself or in conjunction with estrogen determined a raise in prolactin messenger RNA as opposed to the two other treatments with different combinations. This effect was similar to that produced by metoclopramide in animals with intact ovaries. Estrogen and progesterone, acting independently of each other, were responsible for the increase in the S2 isoform of the prolactin receptor. In the uterus, there was heightened expression of prolactin messenger RNA under the effect of the treatment with metoclopramide or with estrogen and/or progesterone. Oophorectomy caused a greater reduction in expression of the prolactin receptor S1 and S2 isoforms than in the other isoforms. However, the combined estrogen plus progesterone treatment led to an increase in the S3 and L forms of the receptor, while progesterone alone resulted solely in a higher expression of the L form of the prolactin receptor in the endometrium of the castrated mice. CONCLUSION: Our data suggest that metoclopramide treatment induces different changes in the expression of prolactin and its receptors according to whether the effect occurs in the pituitary or the uterus of castrated female mice treated with sex steroids
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Patmastan, Piyanuj. "Comparison of properties of wild-type human prolactin and a potent antagonist." Columbus, OH : Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1061248268.
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Thesis (Ph. D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xv, 163 p.: ill. (some col.). Includes abstract and vita. Advisor: Charles L. Brooks, Dept. of Veterinary Biosciences. Includes bibliographical references (p. 156-163).
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Gould, David R. (David Ross). "Prolactin in human breast cancer." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=41006.
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The function of prolactin in human breast cancer was studied using four different approaches. First, purification and characterization of the prolactin receptor from breast cancer cells indicated that the receptor has a molecular mass of 88 000 Da, 67 000 Da being protein, and the other 21 000 Da presumably carbohydrate. Secondly, prolactin was tested for mitogenic activity in breast cancer in vitro. No consistent mitogenic response to prolactin could be demonstrated in these experiments. Thirdly studies upon the regulation of the prolactin receptor in breast cancer cells indicated that the prolactin receptor is stimulated by lactogen, estrogen and progesterone at the protein level. Estrogen, progesterone, thyroid hormone, and forskolin (but not lactogen) increase prolactin receptor steady state RNA levels, and the phorbol ester PMA and retinoic acid inhibited receptor RNA levels. However, effects at the RNA level were of a much lesser magnitude than effects at the protein level. Mechanisms other than transcriptional regulation alone are likely involved in prolactin receptor regulation. Fourthly, prolactin receptor and prolactin inducible protein/gross cystic disease fluid protein (PIP/GCDFP-15) RNA levels were examined in breast cancer tumors. Highly significant correlations were observed between the prolactin receptor and the progesterone receptor; the prolactin receptor and PIP/GCDFP-15; and PIP/GCDFP-15 and progesterone receptor.
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Amaya, Julieta Esperanza Ochoa. "Efeitos da hiperprolactinemia sobre a inflamação alérgica pulmonar em ratos Wistar." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/10/10133/tde-09052016-143242/.
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Objetivo: Foi investigada a hipótese da hiperprolactinemia modular a resposta inflamatória alérgica pulmonar em ratos machos e em fêmas lactantes sem tratamento de domperidona. Métodos: Em ratos machos, a hiperprolactinemia foi de curta duração (5 dias) induzida pela domperidona (5,1 mg.kg-1 por dia, i.p). A resposta alérgica foi gerada por sensibilização e desafios inalatórios com ovoalbumina. Foi feita contagem de leucócitos totais e diferenciados do lavado bronco alveolar (BAL), lavado medular femoral (BFL) e sangue; a percentagem de produção de muco e colageno no pulmão, níveis de corticosterona e prolactina e citocinas TNF-α, IL-4, IL-6, IL-10, em explantes de pulmão e IFNg no BAL, foram medidos. Pela citometria foram avaliadaos os receptores de prolactina; Resultados: Hiperprolactinemia de curta duração feita antes do desafio inalatório disminuiu a resposta alérgica pulmonar na contagem de leucócitos no lavado broncoalveolar. Esse tratamento reduziu a celularidade no BFL e a percentagem de muco e aumentou a expressão de citocinas IL-4, IL-6, IL-10, TNFα e da expressão do IFNg. Níveis altos de prolactina diminuiram o número de eosinófilos ao pulmão no BAL. Pela citometria revelou-se que além de ter menor número de granulócitos migrados ao pulmão, estes apresentaram maior expressão do número de receptores por granulócito para prolactina no grupo tratado com domperidona. Alterações similares foram reveladas em fêmeas lactantes como foi a diminuição nos leucócitos do BAL, e no número de células do BFL. O tratamento profilático diminuiu a resposta alérgica tanto no grupo hiperprolactinêmico como no grupo veículo. O tratamento feito após o desafio inalatório não evidenciou alterações relevantes nas variáveis medidas. Conclusões: A hiperprolactinemia de curta duração, feita após a sensibilização e antes da inalação diminui a resposta inflamatória no pulmão em ratos. Os resultados deste estudo demonstram que a hiperprolactinemia induzida antes do desafio antigênico diminue a inflamação alérgica pulmonar. Assim, é provável que a prolactina endógena tenha um papel relevante como um imunomodulador da asma. Este estudo aponta a possibilidade futura do uso da domperidona para pacientes asmáticos. Durante a primavera muitas espécies de mamíferos têm seus filhotes e ocorre abundância de fatores alergenos no ar. Logo, um fator endógeno que favoreça a proteção de fêmeas durante a lactação, tal como a hiperprolactinemia, tem elevado valor adaptativoObjective: It was investigated if hyperprolactinemia has modulatory actions on lung allergic inflammatory response in male rats. Lactating female rats were tested for pulmonary allergy as well. Methods: In male rats, short-term (5 days) hyperprolactinemia was induced by domperidone (5.1 mg.kg-1 per day, ip). Allergic response was generated by sensitization and inhalation challenge with ovalbumin. Total and differential leukocytes bronchoalveolar lavage (BAL), femoral medullary lavage (BFL) and blood; the percentage of collagen and mucus production in the lungs, plasma levels of corticosterone and prolactin cytokines and TNF-α, IL-4, IL-6, IL-10, IFNg explants lung and BAL, were measured. Flow cytometry was used to evaluate prolactin receptor; Results: Short-term hyperprolactinemia made before the inhaled challenge reduced the pulmonary allergic response in white blood cell counts in BAL. This treatment reduced the cellularity in BFL and the percentage of mucus and increased expression of cytokines IL-4, IL-6, IL-10, TNFa and IFNg expression. High prolactin levels decreased the number of eosinophils to the lung in BAL. There were fewer granulocytes migrated to the lung. These granulocytes showed higher expression prolactin receptors in hyperprolactinemia animals. Similar changes were revealed in lactating females. In these animals, there was a reduction in BAL leukocyte, and the number of cells BFL. Prophylactic treatment decreased the allergic response in both hyperprolactinemic and vehicle groups. The treatment made after inhalational challenge did not induce significant changes in the variables measured in this study. Conclusions: Short-term hyperprolactinemia, made after sensitization and before inhalation, decreases the inflammatory response in the lung of rats. The results of this study demonstrate that hyperprolactinemia, induced before antigen challenge, decreases pulmonary allergic inflammation. Thus, it is probable that the endogenous prolactin has an important role as an immunomodulator of asthma. This study points out the prospect of a future use of domperidone for asthmatic patients. For various mammalian species, parturition occurs during springtime. Pollen in the air might be an abundant allergic factor during springtime. Thus, protecting lactating females against this type allergy might have high adaptive value
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Arthuso, Fernanda dos Santos. "Adaptação de células CHO secretoras de prolactina humana e seus antagonistas para o crescimento em suspensão." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-20062011-110202/.
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O Grupo de Hormônios do Centro de Biotecnologia do IPEN desenvolveu várias linhagens de células de ovário de hamster chinês (CHO) modificadas geneticamente e comprovadamente eficientes na expressão de proteínas heterólogas, dentre elas a prolactina humana (hPRL) e os análogos antagonistas de prolactina (S179D-hPRL e G129R-hPRL). No entanto, todas as linhagens para expressão são cultivadas em monocamadas e dependentes da presença de soro fetal bovino (SFB) no meio de cultivo para um crescimento eficiente. As células em suspensão apresentam um grande interesse industrial-farmacêutico, tanto pela facilidade de cultivo e ampliação de escala, como pela produtividade volumétrica. Desenvolvemos um protocolo para adaptação de células CHO para o crescimento em suspensão e também processos de produção em frascos spinners. Nesse trabalho foi realizada a adaptação das linhagens produtoras de hPRL; S179D-hPRL e G129R-hPRL para o crescimento em suspensão e em meio livre de SFB. Realizamos também a produção em escala laboratorial com as três linhagens adaptadas, assim como a correspondente purificação e caracterização de quatro proteínas heterólogas, incluindo a prolactina humana glicosilada (G-hPRL).The Hormone Group of the Biotechnology Center of IPEN has developed different cells lines of genetically modified chinese hamster ovary cells (CHO) for the expression of heterologus protein like human prolactin (hPRL) and its analogs/antagonists (S179D-hPRL and G129R-hPRL). All cell lines for expression are however cultured in monolayer culture dish and depend on fetal bovine serum (FBS) in the medium for an efficient growth. Cells in suspension show a great industrial-pharmaceutical interest, especially for the cultivation facility and scale enlargement as well as for volumetric productivity. We developed a protocol for adapting CHO cells to suspension growth, in spinner flasks. The adaption of our cell lines producing hPRL; S179D-hPRL and G129R-hPRL to suspension growth and in serum-free medium was obtained. We also carried out laboratory scale production with the three suspension-adapted culture line cells and the corresponding purification and characterization of four heterologous proteins, including glycosylated human prolactin (G-hPRL).
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Constantino, Flávia Bessi. "Relativa influência da prolactina, sua inibição e combinação com testosterona sobre a próstata de ratos castrados comparação entre recrescimento glandular, diferenciação celular e atividade secretora /." Botucatu, 2017. http://hdl.handle.net/11449/148973.
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Orientador: Luis Antonio Justulin JuniorResumo: A próstata é uma glândula do sistema genital masculino que possui grande importância na fertilidade. Estudos clássicos evidenciaram que para que se inicie o desenvolvimento prostático é necessário a presença de andrógeno produzido pelos testículos fetais. Porém, além da estimulação androgênica, estudos apontam para outros hormônios que também atuam na próstata como a Prolactina (PRL). PRL é um hormônio que é principalmente secretado por células lactotróficas da hipofise anterior e está envolvido em muitos processos biológicos, incluindo lactação e reprodução. Assim, investigamos se a modulação da sinalização PRL altera a morfofisiologia da próstata ventral (VP) em ratos castrados. Os ratos Sprague Dawley adultos (n = 6) foram castrados e após 21 dias divididos em 10 grupos experimentais: Castrado Controle (CC): animais castrados que não receberam tratamento; Castrado+testosterona (T): animais castrados que receberam T (4mg / kg); Castrado+PRL (PRL): animais castrados recebendo PRL (0,3 mg / kg); Castrado+T+PRL (TPRL): animais castrados que receberam associação de T e PRL; e Castrado+BR (BR): animais castrados que receberam Bromocriptina (BR) (0,4mg / kg). Grupo Controle: animais intactos (CTR). Os animais foram tratados durante 3 ou 10 dias consecutivos. Ao fim dos tratamentos, os animais foram anestesiados, eutanizados e a prostata ventral (VP) foi removida, pesada e processada para análise histológica e Western blot. O peso corporal não se alterou entre os grupos experiment... (Resumo completo, clicar acesso eletrônico abaixo)
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Glezer, Andrea. ""Estudo da atividade biológica da macroprolactina humana em células Nb2 e em células Ba/F-03 transfectadas com o receptor de prolactina humano forma longa"." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-12042006-085305/.
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A macroprolactinemia é condição freqüente na hiperprolactinemia e em geral, sem impacto clínico. Os dados sobre a atividade biológica da macroprolactina (bbPRL) são controversos e baseados em bioensaio heterólogo com células de rato Nb2. A atividade biológica da bbPRL é observada in vitro e não in vivo, provavelmente porque seu alto peso molecular evita sua passagem pelos capilares. A bioatividade da bbPRL talvez varie de acordo com a especificidade do receptor de prolactina (PRLR). Avaliamos a bioatividade da bbPRL de indivíduos macroprolactinêmicos (Grupo I, n = 18) e da PRL monomérica (mPRL) de pacientes hiperprolactinêmicos sem bbPRL (Grupo II, n = 5) em Nb2 e em células Ba/F-LLP, transfectadas com o PRLR humano. Enquanto ambos ensaios apresentam resultados similares para a atividade de mPRL, nossos resultados indicam que a atividade da bbPRL é presente em ensaio heterólogo e não em ensaio homólogo. O ensaio Ba/F-LLP é sensível e apresenta melhor correlação com a atividade in vivo da bbPRLMacroprolactinemia is a frequent finding in hyperprolactinemic individuals, usually without clinical impact. Data on biological activity of macroprolactin (bbPRL) is mostly based on a heterologous bioassay (Nb2 cell). Biological activity of bbPRL observed in vitro but not in vivo maybe due to its high molecular weight preventing its passage through capillary barrier. Alternatively, bbPRL bioactivity may differ depending on the PRL receptor species specificity. BbPRL from macroprolactinemic individuals and monomeric PRL (mPRL) from hyperprolactinemic patients without macroprolactinemia were tested in two bioassays: Nb2 and in Ba/F-LLP, which expresses human prolactin receptor. While both bioassays achieve similar results considering mPRL activity, our results indicate that bbPRL displays activity in a heterologous but not in a homologous bioassay, consistently with the apparent absence of bbPRL bioactivity in vivo
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Albinsson, Agneta. "Serotonin receptors in the regulation of prolactin release and some behaviors in the rat." Lund : Dept. of Zoophysiology, University of Lund, 1995. http://catalog.hathitrust.org/api/volumes/oclc/38865664.html.
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Bédécarrats, Grégoy. "Studies on variants of prolactin in the turkey." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35854.
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Changes in the pituitary content of prolactin (PRL) and in the ratio of immunoreactive forms of PRL were measured during a reproductive cycle in turkey hens. Low levels of PRL were observed in pituitary glands from sexually immature, out-of-lay and moulting hens. Higher levels were present during the egg laying period and the highest levels were detected in hens expressing incubating behaviour. Two immunoreactive bands of apparent molecular weights of 24 and 27 kDa were visualised on western blots, corresponding to the non-glycosylated (NG-) and glycosylated (G-) forms of PRL, respectively. The percentage of G-PRL was about 60 in sexually immature and egg laying hens. In pituitaries from incubating, out-of-lay and moulting hens the percentage of G-PRL was about 70, 38 and 33, respectively. Thus, higher percentages of G-isoforms (27 kDa) were associated with high levels of total PRL and Iower percentages were associated with low levels of PRL content in the pituitary gland. Digestion of the isoforms with N-glycosidase F resulted in a single band with an apparent molecular weight of 24 kDa. Partial deglycosylation was achieved using neuraminidase, whereas digestion with O-glycosidase had no apparent effect on the isoforms. Thus, G-PRL has N-linked carbohydrates containing sialic acid. In order to study the in vitro release of the PRL isoforms, pituitary glands from turkeys at various physiological stages were stimulated by cVIP in a perifusion system. Total PRL content and the ratio of immunoreactive PRL isoforms in the perifusate were monitored. All the perifused pituitaries responded to cVIP stimulation by increasing the release of PRL. Two immunoreactive bands corresponding to the ones detected in pituitary extracts were detected by western blotting. The G-PRL (27 kDa) was predominant in samples from egg laying and incubating hens and the NG-PRL (24 kDa) was predominant in samples from out-of-lay and moulting hens. No change in the ratio of isoforms released wasA competitive reverse transcription polymerase chain reaction assay was developed in order to semi-quantify the PRL mRNA in individual pituitary glands from turkey embryos and poults. Pituitary content and plasma levels of PRL were also monitored, and the PRL isoforms present in the pituitary gland were detected. The levels of PRL mRNA remained low until five days before hatching, increased until the day of hatch, plateaued during the first three days of age and significantly increased at two weeks of age. Similar changes were observed in pituitary content and plasma concentrations of PRL which were highly correlated. Two immunoreactive bands corresponding to the NG- and G-PRL detected in adult pituitary gland were visualised on western blots. The percentage of G-PRL in pituitary glands were 31.5, 48.6, 48.0 and 56.2 at 22 and 27 days of incubation and at I and 7 days of age, respectively. Thus, higher percentages of G-PRL (27 kDa) were associated with higher levels of total PRL in the pituitary gland.
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Suzuki, Miriam Fussae. "Síntese e caracterização de prolactina de camundongo (mPRL) e deu seu análogo (S177D-mPRL)." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-29062011-154905/.
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A prolactina é um neurohormônio que faz parte da superfamília das citocinas e está envolvida em inúmeros processos biológicos. Devido à sua ação endócrina, autócrina e parácrina, a prolactina está muitas vezes relacionada ao desenvolvimento de patogenias humanas como carcinomas e doenças autoimunes. Considerando-se que: a) diferença de 41% encontrada na sequência de aminoácidos da prolactina de camundongo em relação à humana, b) diferenças na glicosilação, fosforilação, e ligação ao receptor e, c) o fato que os modelos animais utilizados em ensaios in vivo com prolactina humana são geralmente ratos ou camundongos (modelos heterólogos), fica evidente que esses fatores podem interferir na interpretação dos resultados. Portanto, experimentos em sistemas homólogos seriam desejáveis. Esse trabalho descreve a obtenção pela primeira vez da mPRL no espaço periplásmico bacteriano, portanto na sua forma autêntica, ou seja, sem a metionina inicial, com expressão de 0,1 ± 13,2% g/mL/A600. Para isso um vetor de expressão baseado no promotor lPL foi construído e utilizado como promotor constitutivo, com ativação a 37° C. Um processo de fermentação em biorreator, com rendimentos de expressão de até 2,5 g/mL, e um processo de purificação com três etapas: concentração e purificação por hidrofobicidade (Phenyl Sepharose CL-4B) seguida por HPLC de fase reversa e HPSEC, foram também desenvolvidos. A mPRL purificada foi caracterizada por técnicas físico-químicas e biológicas em comparação com o padrão de referência da mPRL recombinante do Instituto Nacional de Saúde (NIH, EUA). A atividade biológica foi analisada e sua potência calculada foi de 33,9 ± 1,4 UI/mg. O mesmo vetor foi utilizado para a expressão do antagonista S177DmPRL, mas o baixo nível de expressão obtido inviabilizou a sua produção no espaço periplásmico de bactérias. Como alternativa, optamos por produzir essa proteína em células CHO e clones com expressão da ordem de 1 g/mL/dia foram obtidos. Com a expressão tanto da mPRL autêntica, como do S177D-mPRL, está aberto o caminho para o desenvolvimento dos estudos que envolvam modelos animais onde a mPRL e seu antagonista sejam fatores relevantes a serem considerados.Prolactin is a neurohormone included in cytokine superfamily and involved in innumerous biological processes. Due to its endocrine, autocrine and paracrine action, it is, frequently, related to development of human pathologies, such as carcinomas and autoimmune diseases. Considering some factors: a) the difference of 41% between the amino acid sequence of mouse prolactin in relation to the human one, b) glycosylation, phosphorylation and receptor ligation differences, and c) the fact that the animal model used for in vivo assays with human prolactin are generally rats or mice (heterologous), it is evident that these factors might interfere in the interpretation of results. Therefore, experiments with homologous systems are desirable. This work describes, for the first time, the expression of mouse prolactin in the periplasmic space of bacteria, in its authentic form, i. e., without initial metionine, showing expression levels of 0.1 ± 13.2% g/mL/A600. For this purpose, an expression vector based on PL promoter was constructed and used as a constitutive form, with activation at 37° C. A fermentation process in bioreactor, with expression yields up to 2.5 g/mL, and purification process with three steps: concentration and purification by hydrophobicity (Phenyl Sepharose CL-4B) followed by reverse phase HPLC and HPSEC, were also developed. The mPRL was purified and characterized by chemo physical and biological techniques compared to the recombinant standard reference from the National Institute of Health (NIH, USA). Its biological activity was analyzed and the calculated potency was 33.9 ± 1.4 UI/mg. The same vector was used for the expression of S177D-mPRL antagonist, but the low expression level obtained makes it impracticable to produce this protein in the periplasmic space of bacteria. As an alternative, the S177D-mPRL was produced in CHO cells and clones with expression level of about 1 g/mL/day were obtained. The expression of both proteins, the authentic mPRL and the S177D-mPRL, opens the door for developing studies with animal models if mPRL and its antagonist might be considered relevant factors.
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Resalat-Panah, Nazila. "Characterization of Anp32 in Prolactin Signaling." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114174.
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Prolactin (PRL) and its downstream pathway Jak2/Stat5a are required for mammary gland developement and as well as differentiation of mammary alveolar structures. However, its role in breast carcinoma is still not fully understood. Some recent data including the one generated from our laboratory indicates that PRL may have a suppressive effect on breast carcinogenesis. To further investigate this matter, we performed micro array analysis to examine the PRL target genes in the mouse mammary epithelial cell line (HC11). Based on microarray analysis, we identified the gene Anp32, a small nucleo/cytoplasmic acidic protein, as a downstream target gene involved in PRL signaling. We further confirmed these results using quantitative PCR and western blot analyses. In addition, I have examined the contribution of this protein in regulating PRL signaling leading to activation of the Jak2/Stat5a pathway. The results illustrated that upon PRL stimulation, Anp32a undergoes phosphorylation and translocates to the nucleus. Unexpectedly, I found that PRL stimulation led to Anp32/Stat5 complex formation in mammary epithelial cells. We further confirmed this interaction using co-localization immunofluorescence confocal microscopy studies. Furthermore, using GST fusion proteins of various domains of Anp32 in in vitro association studies we illustrated that Stat5a interaction with Anp32a requires domains which present within both the N and C terminus of Anp32a. In a parallel analysis, to begin to examine the role of Anp32a in breast cancer, we examined the level of Anp32a expression in breast cancer cell lines. Our preliminary results exhibit a reduced expression level of Anp32a in highly metastatic mouse breast cancer cell line 4T1compared to Hc11 mammary cells.La prolactin(PRL) et sa voie de signalisation en aval Jak2/Stat5a sont requies à la croissance de la glande mammaire, ainsi qu'à la différentiation des épithéliales mammaires. Cependant, le rôle de la PRL dans le développement du cancer du sein n'est pas encore clair. Quelques preuves récentes, obtenues par notre laboratoire, montrent que la PRL pourrait supprimer certains aspects de la carcinogenèse du sein. Par consequent, nous avons effectué une analyse de puce à ADN pour examiner les genes cibles de la en utilisant les cellules épithéliales mammaires de souris HC11. Sur la base de l'analyse micro-array, nous avons identifié la protèin Anp32a, une petite nuclèo- protein cytoplasmique acid comme une gene cible impliqué en aval de la voie de signalization de la PRL. Nous avons davantage confirmé ces résultats en utilisant la Reaction de polymerization en chaine (PCR) et l'analyse d'immunobuvardage de type western. En plus, nous avons examiné la contribution de cette protéine dans la régulation de la voie de signalisation de la PRL conduisant à l'activation de la voie Jak2/Stat5a. Les résultats ont montré que Anp32a est transloquée au noyau et deviant phosphorylée par la stimulation de la PRL. En plus, la kinase JAK2 est nécessaire pour la phosphorylation sur les tyrosines de Anp32a.De façon inattendue, nous avons constaté que la stimulation de la PRL conduit à la formation d'un complexe entre les protéines Anp32a/Stat5 dans les cellules épithéliales mammaires. En plus, nous avons confirmé cette interaction en observant la co-localisation par des études d'immunofluorescence par microscopie confocale. En outre, à l'aide des protéines de fusion de GST représentant différentes domains de Anp32 en utilisant des études d'association in vitro, nous avons illustré le fait que Stat5a nécessite les domains qui sont pré sent en N et C terminal. En parallèle, nous avons examiné le niveau d'expression de Anp32a dans les plusieurs lignées cellulaire de cancer du sein. Nos resultats preliminaries, présente un niveau d'expression réduite de Anp32a en cellules cancéreuse mammaires 4T1(hautement métastatiques) par rapport à les cellules épithéliales mammaires HC11.
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歐惠連 and Wai-lin Au. "Molecular characterization of chicken prolactin gene." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31227119.
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Sauvé, Danielle. "Neuroanatomical specificity of prolactin-induced hyperphagia and expression of Fos-like immunoreactivity following central administration of prolactin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0001/NQ39020.pdf.
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BUCKLEY, ARTHUR RALPH JR. "EFFECTS OF PROLACTIN ON BIOCHEMICAL MARKERS OF HEPATIC PRENEOPLASIA IN THE RAT." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/183834.
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Prolactin (PRL) may be a key mammalian growth and developmental hormone. Hepatic receptors bind PRL implicating the liver as a PRL target. Recent evidence suggests that PRL triggers hepatic ornithine decarboxylase (ODC) induction, a marker of a trophic response. This suggests that in the liver PRL may contribute to neoplasia. To test this theory, PRL modulation of plasminogen activator (PA), DNA synthesis, cytochrome P450 (P450), liver hypertrophy and enzyme altered foci (EAF) was assessed. Cyclosporine, a PRL receptor antagonist, attenuated PRL-stimulated PA induction. PRL-stimulation of PA and ODC activity reflected age dependence. PRL administration to young rats stimulated hepatic microsomal P450 content 39% above control, an effect camparable to phenobarbital. Incubation of microsomes from PRL-treated rats with warfarin produced a metabolic pattern unique to PRL. PRL stimulated hepatic DNA synthesis up to 400%. This effect was shown to be specific for hepatic parenchymal cells. PRL for 6 weeks produced hepatic hypertrophy, an effect augmented by diethylnitrosamine (DEN). Additionally, incresed hepatic GGTase activity and EAF were demonstrated in rats treated with chronic PRL after DEN. Extrahepatic neoplasia was increased by partial hepatectomy PH and chronic PRL. PRL receptor coupling was investigated in PRL-dependent Nb₂ node lymphoma cells. ODC induction and proliferation were found to be coupled to protein kinase C (PKC) and calmodulin (CM) in experiments using pharmacological agents. Phosphatidylinositol (PI) turnover and ionic flux alterations were also implicated. These results suggest PRL receptor coupling to PI turnover and PKC activation in Nb₂ cells. PRL may be a key liver growth hormone. PRL induces PA, ODC and P450. Furthermore, its ability to promote EAF strongly implicates PRL in the ontogeny of hepatocarcinogenesis.
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Pinaffi, Fábio Luís Valerio. "Dinâmica hormonal durante o processo luteolítico nas espécies equina e bovina; com ênfase sobre o papel da prolactina." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-16122013-113326/.
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O presente estudo visou caracterizar a secreção de PRL e estudar suas interrelações com a PGFM durante a pré-luteólise, luteólise e pós-luteólise em éguas (Experimento 1); avaliar o efeito da inibição de PRL e PGF2α na luteólise e definir a sincronia entre PRL e PGFM em novilhas (Experimento 2); definir a sincronia entre PRL e PGFM em éguas (Experimento 3); e avaliar a constante estimulação da PRL durante o ciclo estral em éguas (Experimento 4). No experimento 1 em éguas, amostras de sangue foram coletadas durante as 24 h da préluteólise, luteólise e pós-luteólise. As concentrações de PRL e PGFM foram rítmicas, sendo a duração dos pulsos de PRL de 5 h, com intervalos de 7,5 h entre pulsos e 12 h entre picos. Durante a luteólise e pós-luteólise, os pulsos de PRL foram mais proeminentes, as concentrações de PRL durante um pulso de PGFM foram maiores no pico de PGFM e notouse uma maior sincronia entre picos de PRL e PGFM. No experimento 2 em novilhas, as secreções de PRL e PGF2α foram inibidas durante a luteólise. A inibição da PRL associou-se a maiores concentrações de P4 e LH, sem efeito sobre a PGFM. Entretanto, a inibição da PGF2α associou-se a uma queda nas concentrações de PRL. A mensuração da área do CL mostrou-se eficiente em detectar a luteólise. No experimento 3 em éguas, no verão e outono, inibiu-se a secreção de PGF2α e PRL no Dia 14. As concentrações de PGFM foram reduzidas com a inibição de PGF2α, mas não com a inibição da PRL. No verão, a inibição tanto de PRL quanto de PGF2α reduziu as concentrações de PRL. As concentrações de PGFM não diferiram entre o verão e o outono, enquanto que as concentrações de PRL foram menores no outono. No experimento 4 em éguas, estimulou-se a secreção de PRL a cada 8 h. Amostras de sangue foram coletadas a cada 12 h do Dia 13 até a ovulação e a cada hora por 12 h no Dia 14. A estimulação repetida da PRL não aparentou manter as concentrações de PRL elevadas após o Dia 14. Nas amostras a cada hora, concentrações de PRL atingiram um valor máximo 4 horas após a estimulação e os pulsos de PRL foram aumentados. O aumento na PRL não afetou a PGFM, P4 e fluxo sanguíneo do CL. Entretanto, a estimulação da PRL quebrou a sincronia entre PGFM e PRL. Estão contidos nessa dissertação o primeiro relato em éguas sobre a caracterização e ritmicidade de pulsos de PRL, sincronia entre pulsos de PRL e PGFM e maior atividade da PRL durante a luteólise e pós-luteólise. A inibição da PRL interferiu na secreção de P4 em novilhas, mas foi confundida pelo aumento de LH. A sincronia entre pulsos de PGFM e PRL representa um efeito positivo da PGF2α sobre a PRL, tanto em éguas quanto em novilhas.The aim of the present study was to characterize the PRL secretion and study the relationship between PRL and PGFM during preluteolysis, luteolysis and postluteolysis in mares (Experiment 1); evaluate the effect of PRL and PGF2α inhibition on luteolysis and define the synchrony between PRL and PGFM in heifers (Experiment 2); define the synchrony between PRL and PGFM in mares (Experiment 3); and evaluate the frequent stimulation of PRL during the estrous cycle in mares (Experiment 4). On experiment 1 in mares, blood samples were collected during the 24 h of preluteolysis, luteolysis and postluteolysis. Concentrations of PRL and PGFM were rhythmic. Prolactin pulses had 5h of duration, interval of 7,5 h between pulses, and 12 h between peaks. Pulses of PRL were more prominent during luteolysis and postluteolysis. Concentrations of PRL during PGFM pulses differ during luteolysis and postluteolysis, and were greater at the peak of PGFM. The synchrony between peaks of PRL and PGFM was greater during luteolysis and postluteolysis. On experiment 2 in heifers, the secretion of PRL and PGF2α were inhibited during luteolysis. The PRL inhibition was associated with greater concentrations of P4 and LH. The inhibition of PGF2α was associated with a decrease on PRL concentrations, but no effect on PGFM was observed after PRL inhibition. The CL area measurement was an efficient method to target luteolysis. On experiment 3 in mares, in summer and autumn, secretion of PGF2α and PRL were inhibited on Day 14. The inhibition of PGF2α reduced PGFM concentrations. No effect on PGFM was observed after PRL inhibition. Concentrations of PGFM were not different between summer and autumn, and PRL concentrations were low in the autumn. In the summer, PRL inhibition reduced PGF2α concentrations. On experiment 4 in mares, PRL was stimulated every 8 h. Blood samples were collected every 12 h from Day 13 to ovulation, and every hour for 12 h on Day 14. The frequent stimulation on PRL did not appear to maintain higher concentrations of PRL after Day 14. On hourly samples, concentrations of PRL reached maximum value 4 h after stimulation and pulses of PRL were increased. The increase on PRL did not affect PGFM, P4, and blood flow of the CL. The synchrony between PGFM and PRL was partially disrupted by PRL stimulation. This was the first report on characterization and rhythm of PRL pulses, synchrony between PRL and PGFM pulses, and greater PRL activity during luteolysis and postluteolysis. The inhibition of PRL interfered with P4 secretion in heifers, but was confounded by the LH increase. In mares and heifers, the synchrony between PGFM and PRL pulses represents a positive effect of PGF2α on PRL.
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Sivaprasad, Umasundari. "The mechanism of lactogen receptor binding by human prolactin." Connect to this title online, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1054499303.
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Thesis (Ph. D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xiii, 133 p.; also includes graphics (some col.) Includes bibliographical references (p. 124-133). Available online via OhioLINK's ETD Center
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Gaasenbeek, Michelle Lynn. "Regulation of non-pituitary prolactin gene expression." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ32480.pdf.
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Zhou, Jiang Feng. "Characterization of prolactin receptor in Meleagris gallopavo." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0019/NQ44647.pdf.
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Turrone, Peter. "Prolactin response with typical and atypical antipsychotics." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0017/MQ54150.pdf.
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Zhou, Jiang Feng 1964. "Characterization of prolactin receptor in meleagris gallopavo." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35661.
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Prolactin receptor (PRLR) is a membrane anchored protein mediating the biological actions of prolactin. The turkey PRLR (tPRLR) cDNA was isolated and characterized. The open reading frame (ORF) of tPRLR predicted 831 amino acid residues composed of a signal peptide, an extracellular domain (ECD), a single transmembrane domain and an intracellular domain. The deduced amino acid sequence of the turkey prolactin receptor is 53.8%, 51.7%, 49.8%, 49.8%, 80.3% and 89.91% identical to that of the rabbit bovine, human, long form of the rat, pigeon and chicken PRLRs, respectively. The extracellular domain contains two homologous repeat units with 63% amino acid sequence identity to each other. The membrane-distal and membrane-proximal repeats were 53--60% and 62--70% identical to the ECDs of the mammalian PRLRs, respectively. A tPRLR transcript with a molecular size of 3 kilo nucleotides was identified and was detectable in 26 tissues examined. The pituitary gland, crop sac, duodenum and gizzard were found to express the highest levels of tPRLR mRNA among the 26 tissues. In most tissues examined there was no obvious relationship between blood levels of PRL, reproductive states and estimated concentrations of the receptor mRNA. However, in the hypothalamus, increasing blood levels of PRL were associated with decreasing levels of receptor transcripts (p < 0.05), whereas, the opposite relationship was observed in the pituitary gland (p < 0.05). The extracellular domain of tPRLR (tPRLR-ECD) was expressed as a GST fusion protein (tPRLR-ECD-GST) in E. coli. The expression of tPRLR-ECD-GST in BL21 strain yielded a protein with a molecular mass of 76 kDa. About 99% of the fusion protein was present in inclusion bodies and about 50% of the total protein in inclusion bodies was the fusion protein. The insoluble fusion protein was denatured, refolded and purified using GST affinity chromatography. The yield of the purified fusion protein was 20 mg per liter with an estimated p
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Rozakis-Adcock, Maria. "Structurefunction analysis of the rat prolactin receptor." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=41027.
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In order to investigate the structure/function relationships of the prolactin (PRL) receptor family, two complementary approaches were employed: that of site-specific mutagenesis and chimeric receptor constructs with the homologous growth hormone (GH) receptor. We initiated our studies by first attempting to define structural features in the extracellular domain that were involved in ligand-receptor interactions. Binding studies of transiently expressed rat PRL receptor mutants established that the first four cysteine residues conserved among all members of the cytokine/GH/PRL receptor superfamily are crucial for ligand binding and contribute to the structural integrity of the receptor protein. Moreover, charged residues within the first disulfide-linked loop as well as a set of lactogen-specific sequences between the two pairs of cysteines were shown to be key determinants of PRL binding specificity. Conversely, the second disulfide loop did not appear to participate in ligand-binding interactions with either oPRL or hGH. A phenylalanine residue highly conserved among all members of the GH/PRL receptor subfamily and lying adjacent to the fourth cysteine was also shown to be indispensable for the binding activity in both somatogenic and lactogenic receptors and is thus postulated to confer the loss-of-function phenotype observed in certain patients with Laron-type dwarfism in which the phenylalanine residue in the GH receptor has been substituted to a serine. Finally, the WSXWS motif, another hallmark of the cytokine/GH/PRL class of receptors which lies proximal to the transmembrane domain, was shown to be necessary for high affinity binding of the PRL receptor to oPRL and hGH, perhaps by providing a contact site for the formation of a dimeric high affinity complex. Structure/function analysis of the cytoplasmic domain demonstrated that it not only influences hormone binding but also regulates the cellular distribution of the PRL receptor. A putative internalizat
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Ho, Ming-Kai 1978. "Characterization of glycosylation of prolactin in galliformes." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98724.
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Prolactin (PRL) is a highly versatile hormone in terms of its biological functions. In Galliformes, high levels of PRL are associated with incubation behaviour and hatching. It has been shown that these high levels of PRL were associated with an increased ratio of glycosylated PRL (G-PRL) versus non-glycosylated PRL (NG-PRL) in turkey (Bedecarrats et al., 1999a). This suggests that glycosylation of PRL is related to its proper function during those stages of life. However, the mechanism(s) controlling post-translational modification of PRL are unknown. In order to investigate genes associated with the glycosylation of PRL, an in vitro study was undertaken. The pituitary glands of day 24 turkey embryos (n=60) were collected and pooled into two groups which were incubated in medium 199 for 4 hours in the absence or presence of 10-7 M vasoactive intestinal peptide (VIP). Western blot analysis of PRL was used to assess the response of the pituitary glands to the VIP stimulation. As expected, the absolute level of PRL as well as the percentage of glycosylated PRL isoform increased following stimulation with VIP. The mRNA of both stimulated and non-stimulated samples were extracted and reverse transcribed into cDNA. Using suppression subtractive hybridization (SSH), a cDNA subtractive library which only contained differentially expressed cDNAs between VIP stimulated and non-VIP stimulated turkey pituitary glands was constructed. Seventeen percent of the genes from the library are related to cell proliferation and apoptosis. Ten genes were selected for real-time PCR analysis. The functions of these genes and their potential roles in response to the stimulation by VIP and glycosylation of PRL are discussed.
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LaPensee, Christopher Ryan. "METABOLIC FUNCTIONS OF PROLACTIN IN THE MOUSE." University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1172587296.
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Christensen, Heather R. "Molecular and Integrated Systems Physiology of Prolactin." University of Cincinnati / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040076.
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Hyde, Jennie. "The Role of Prolactin in CCL28 Regulation." BYU ScholarsArchive, 2007. https://scholarsarchive.byu.edu/etd/1305.
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Infants are born with naive immune systems, making them susceptible to a variety of infections. In order to protect the newborn infant it is important that mothers be able to pass protective IgA antibodies to their infants through breast milk. B cells that produce IgA enter the mammary tissue during lactation and secrete IgA into the milk. During pregnancy, the mammary tissue expresses high levels of chemokines, molecules that allow lymphocytes to selectively home to specific tissues. The chemokine CCL28 has been shown to be upregulated during both pregnancy and lactation, and is vital for the ability of IgA-producing B cells to home to the mammary tissue during lactation. The aim of this study was to determine whether CCL28 expression is regulated by prolactin signaling.
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Hui, Mei-yee Angela, and 許美儀. "Molecular characterization of the chicken prolactin receptor gene." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31228227.
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Wang, Ying, and 王莹. "Molecular and functional characterization of the prolactin receptor, prolactin-releasing peptide receptor, and growth hormone-releasinghormone receptor genes in chicken." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39556864.
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Oliveira, Taís Lima de. "Desenvolvimento de processo de fermentação em biorreator para produção de prolactina humana secretada no espaço periplásmico de Escherichia coli." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-07072009-152955/.
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A Prolactina (PRL) é um dos hormônios mais versáteis em termos de ação biológica. Sua ação mais conhecida está relacionada com o estímulo da lactação e regulação do crescimento e da diferenciação da glândula mamária; também apresenta importante aplicação diagnóstica. Somando os crescentes estudos sobre suas possíveis aplicações terapêuticas, fica cada vez mais notória a necessidade da obtenção desse hormônio puro, biologicamente ativo e na sua forma autêntica.O objetivo fundamental desse projeto foi a produção de hPRL em escala laboratorial a partir de bactérias (E.coli) modificadas geneticamente, utilizando um sistema de expressão baseado no promotor Lambda () PL, o mesmo utilizado com sucesso em nosso laboratório na expressão do hGH. Descrevemos nesse trabalho um processo de cultivo em biorreator, onde não foi utilizado o repressor cIts, uma proteína termo-sensível que usualmente é utilizada para inibir o funcionamento do promotor PL durante crescimento a 30ºC. O processo de cultivo apresenta basicamente três etapas: na primeira etapa o crescimento é realizado sem adição contínua de nutrientes (cultivo em batch), na segunda etapa ocorre adição contínua de nutrientes e carboidrato (cultivo em fed-batch) e na última etapa é realizada a ativação, caracterizada pelo aumento da temperatura mantendo-se a adição de nutrientes e carboidrato. Esse processo de fermentação rápido e flexível, com duração média de 20 horas, permitiu obter uma biomassa final correspondente à densidade óptica de aproximadamente 30 A600nm (unidades ópticas de absorbância em 600nm) e com uma expressão da ordem de 1g de hPRL mL-1 A600 -1, as mais altas já relatadas para secreção de prolactina no espaço periplásmico. A hPRL monomérica foi purificada e caracterizada por métodos físico-químicos e biológicos, os quais confirmaram a sua atividade biológica e imunológica, o seu correto processamento e uma massa molecular relativa (Mr) de 22.906.Prolactin (PRL) is one of the most versatile hormones in terms of biological action. His best known action is related to the stimulation of lactation and regulation of growth and differentiation of the mammary gland; it also has wide important diagnostic applications. Considering all the increasing studies on its potential therapeutic applications, the need for obtaining this hormone in its pure, biologically active and authentic form becomes clearer and clearer. The fundamental objective of this project was the production of hPRL on the laboratory scale, from genetically modified bacteria (E.coli), using an expression system based on Lambda () PL promoter, the same successfully used in our laboratory for the expression of hGH. We set up a cultivation process in bioreactor, where the repressor (cIts), a thermo-sensitive protein that is usually used to inhibit the PL promoter during the growth phase (30°C). The cultivation process presents basically three stages: the first step in was not used the growth is carried out without the continuous addition of nutrients (batch cultivation), the second step in which a continuous addition of nutrients and carbohydrate occurs (fed-batch cultivation) and a final step when activation is carried out. The latter is characterized by an increased temperature, still maintaining the addition of nutrients and carbohydrate. This fast and flexible process of fermentation, with the average duration of 20 hours, led to a final biomass of approximately 30 A600nm (units of optical absorbance at 600nm), with the expression of about 1g of hPRL mL-1A600 -1, the highest ever reported for the secretion of prolactin in the periplasmic space. Monomeric hPRL was purified and characterized by physical-chemical methods and biological assays, which confirmed its biological and immunological activity, correct processing and a relative molecular mass (Mr) of 22,906.
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Gregory, Susan Jan. "The intrapituitary regulation of fertility in the seasonal breeder." Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247177.
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Almgren, Colleen Marie. "The potential role of potent prolactin antagonists as chemotherapeutics for human cancers an evaluation of select prolactin antagonists in human breast cancer cells /." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1104778150.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xx, 199 p.; also includes graphics (some col.) Includes bibliographical references (p. 178-199).
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Bédécarrats, Grégoy Yves. "Studies on variants of prolactin in the turkey." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0028/NQ50110.pdf.
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Diogenes, Anibal. "Prolactin modulation of trigeminal sensory neurons : a dissertation /." San Antonio : UTHSC, 2006. http://proquest.umi.com/pqdweb?did=1246523531&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Katoh, Masao. "Biochemical and immunological characterization of the prolactin receptor." Thesis, McGill University, 1985. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=73962.
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Grosser, Peter M. "Testosterone modulation of plasma gonadotropin and prolactin patterns." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75750.
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The neuroendocrine sites and mechanisms of action whereby testosterone (T) regulates LH, FSH and prolactin signals in male rats were investigated by determining the effects of orchidectomy and graded T replacement on the secretion patterns of these hormones in blood. A chronic jugular catheter system was established to obtain blood samples at 5-10 min intervals from unrestrained, unanesthetized rats; this enabled moment to moment changes in plasma hormone concentrations, and thus hormone patterns, to be determined. In intact rats the patterns of LH and prolactin in plasma are pulsatile, but exhibit no synchrony; the FSH pattern shows no pulses. Post-orchidectomy LH concentrations rise due to increases in pulse amplitude and frequency; FSH also rises, but still no pulses are detected. Decreased prolactin pulse amplitudes result in lower plasma concentrations, despite an increase in pulse frequency. Treatment of orchidectomized rats with low doses of T increases mean LH and FSH concentrations, thus demonstrating that T is capable of exerting a positive feedback effect in males. The effect on LH is due to a stimulation of LH pulse amplitude which is not mediated at the pituitary. The FSH pattern becomes pulsatile and is synchronized with that of LH. Higher doses of T exert negative feedback on LH and FSH; LH pulse amplitude and frequency are decreased and the FSH pattern once again shows no pulses. These effects of T are partially due to inhibition of the pituitary response to LHRH. Low doses of T completely block the effects of orchidectomy on prolactin pulse amplitude, but T levels similar to those in intact animals are required to reverse the accelerated pulse frequency. The results suggest that gonadotropins and prolactin are regulated by separate pulse generators, each responsive to changes in plasma T. Furthermore, T, depending on its concentration, regulates gonadotropin and prolactin secretion by exerting stimulatory and/or inhibitory effects on various neur
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Dowell, Kenneth. "Prolactin molecular heterogeneity in normoprolactinaemic and hyperprolactinaemic serum." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305105.
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Gilbert, Mark Simon. "The expression of human prolactin in Escherichia coli." Thesis, University of Reading, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238668.
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Kurima, Kiyoto. "Transcriptional regulation of the prolactin gene in turkeys." Diss., Virginia Tech, 1996. http://hdl.handle.net/10919/37773.
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Poor reproductive performance by turkey hens compared with chickens is partially due to the early cessation of egg production associated with the onset of incubation behavior. Prolactin (Prl) is involved in the induction and maintenance of incubation behavior in birds, and understanding the regulatory mechanism(s) of Prl gene expression will provide fundamental information to manipulate Prl production for better reproductive performance in turkey hens.Ph. D.
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Hyde, Jennie. "The role of prolactin in regulating CCL28 expression /." Diss., CLICK HERE for online access, 2007. http://contentdm.lib.byu.edu/ETD/image/etd1717.pdf.
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Vander, Hamm Dale Gene 1954. "Prolactin regulation of lymphocyte proliferation: An early event." Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/282723.
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It has been suggested by immune system studies that pituitary prolactin (PRL) may have an immunomodulatory role and that lymphocytes themselves may produce prolactin-like proteins (Ly-PLP). The studies in this dissertation focused on Ly-PLP production and PRL/Ly-PLP actions in an enriched population of rat splenic T helper (TH) CD4 and cytotoxic CD8 cells. Studies were planned on a dual hypothesis: first, that T-cells produce Ly-PLP which may act in an autocrine manner and second, that Ly-PLP may be necessary for interleukin 2 (IL-2) production. To study the possible mechanisms by which PRL and Ly-PLP regulate lymphocyte proliferation, a PRL-free medium was used and a polyclonal antibody to rat PRL (A-PRL) was used to inactivate the residual PRL and the expressed Ly-PLP in the cell culture system. This antibody inhibited T-cell proliferation in both a time and a concentration-dependent manner. Based on four lines of evidence, the in vitro inhibitory activity of A-PRL on cell proliferation appeared to be modulated in part by inhibition of IL-2 production. First, the A-PRL induced inhibition of T-cell proliferation was overcome by addition of recombinant human IL-2 (rhuIL-2). Second, A-PRL treatment of mitogen stimulated T-cells was shown by RT-PCR analysis to inhibit IL-2 mRNA expression. IL-2 receptor beta (IL-2rB) mRNA, which is constitutively expressed in T-cells, was not inhibited. Third, A-PRL inhibited IL-2 protein production in a concentration dependent manner. Fourth, the A-PRL induced inhibition of IL-2 production was overcome by preincubation of the A-PRL with purified rat pituitary PRL (rPRL). Dot Blot and RT-PCR analysis data in this dissertation were suggestive but were inconclusive in support of the hypothesis that rat lymphocytes and specifically T-cells constitutively express mRNA for PRL and/or Ly-PLP. Western blot studies of T-cell lysates suggested that rat T-cells express a Ly-PLP with the apparent molecular weight 46 kD, as well other variants. In summary the data presented in this dissertation indicate that rat T-cells expressed Ly-PLP and treatment with A-PRL to inactivate Ly-PLP inhibited cell proliferation, expression of IL-2 mRNA, and IL-2 protein expression by CD4 cells. The inhibition of IL-2 production was the likely mechanism by which A-PRL binding of Ly-PLP inhibited mitogen induced T-cell proliferation in rats. The inhibition of IL-2 production suggests that extracellular pituitary PRL or Ly-PLP through a hormone and/or an autocrine mechanism respectively may be necessary but not sufficient for the induction of IL-2 mRNA and IL-2 protein expression in activated rat T-cells.
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Larsen, Caroline, and n/a. "Pheromones, prolactin and maternal behavior : (male pheromones initiate prolactin-induced neurogenesis, decrease anxiety and advance maternal behavior in virgin female mice)." University of Otago. Department of Anatomy & Structural Biology, 2007. http://adt.otago.ac.nz./public/adt-NZDU20071019.134553.
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Maternal behavior in rodents is dependent, at least in part, on prolactin acting in the brain. Pheromones carried by male mouse major urinary proteins lower serum prolactin levels in female mice. Therefore, we hypothesized that virgin female C57BL/6J mice housed in split cages, where they had pheromonal but not physical contact with a male, would show suppressed maternal behavior. Contrary to our hypothesis, we found split-cage housed females were significantly faster to retrieve 3 foster pups on the first and second day of maternal behavior testing compared to mice housed in individual cages. The advancement in maternal behavior was replicated when virgin females were simply exposed to male mouse urine-soaked bedding. Ovariectomising the mice, to remove the influence of steroid hormones, prior to placement in the split cages, prevented the pheromonal advancement of maternal behavior. The data infer that an ovarian steroid-dependent action of male mouse pheromones primes virgin female mice to express maternal behavior more rapidly when mouse pups are introduced.
This effect required greater than 14 days exposure to male pheromones. Male mouse pheromones are reported to suppress prolactin secretion. However, serum prolactin levels in split-caged housed females, where they had pheromonal but not physical contact with a male, were only briefly lowered and became significantly elevated from 24 hours until 72 hours of pheromonal contact. Despite the early increases in prolactin after pheromone exposure, levels were significantly lower in the pheromone-exposed females when maternal behavior was tested after 21 days. It has been previously reported that prolactin is important in the onset of maternal behavior, but is not required for the ongoing maintenance of maternal behavior. We hypothesised that the hyperprolactinemia observed in the first 24-72 hours of pheromonai exposure had subsequently led to the enhanced maternal behavior. To test this we injected a group of individually-housed mice with slow release prolactin for 48 hours to simulate the period of hyperprolactinemia, and blocked prolactin secretion in a group of split-caged housed females with bromocriptine, and tested their maternal behavior 18 days later. The mice injected with prolactin had enhanced maternal behavior, compared to controls injected with a placebo. By contrast, bromocriptine inhibition of prolactin secretion completely prevented the pheromonal enhancement of maternal behavior. This suggests that the pheromonal advancement of maternal behavior is specifically mediated by a 48-hour period of sustained hyperprolactinemia.
It has been previously shown that pregnancy increases neurogenesis in the subventricular zone in a prolactin-dependent manner. Therefore, as the male pheromone-induced advancement of maternal behavior is prolactin-dependent and takes some time to occur, we hypothesized that long-term pheromonal contact initiates mitogenesis in the subventricular zone. Split-caged housed mice showed a significant increase in BrdU-labeled cells in the subventricular zone after 7 days of contact which reduced to baseline levels by 14 days of contact. The mice injected with BrdU on day 7 of contact and killed 21 days later showed a significant increase in labeled cells in the accessory olfactory bulb compared to controls. The data suggest that male mouse pheromones initiate mitogenesis in the subventricular zone of virgin C57B6 mice, in an exposure-dependent manner, and that these cells travel via the rostral migratory stream to the accessory olfactory bulb. As with the effect on maternal behavior, the pheromone-induced increase in neurogenesis was steroid- and prolactin-dependent.
During pregnancy and lactation in rodents, prolactin receptor expression is increased in the MPOA, an adaptive change, which could lead to an increased neuronal response to serum prolactin levels, which are high just prior to parturition, and consequently could underlie the enhanced maternal responses seen in late pregnancy and after parturition. It is known that systemic prolactin can access the brain, but it is also possible that there could be local synthesis of brain prolactin acting in an autocrine or paracrine manner. Therefore we hypothesized that the pheromonal-induced changes in maternal behavior are being mediated by altered prolactin receptor expression/sensitivity and/or increased production of brain prolactin. Using RT-PCR to measure levels of prolactin receptor and prolactin mRNA, we found changed expression of the 3 short forms and the long form of prolactin receptor mRNA in the arcuate nucleus, paraventricular nucleus, bed nucleus of the stria terminalis, and MPOA with either exposure to male pheromones or pups. We also found changes in prolactin mRNA in the MPOA and paraventricular nucleus after exposure to pups or male pheromones. The data suggest that altered levels of expression of the receptor, coupled with local production of brain prolactin acting in an autocrine or paracrine manner, may cause a net change in prolactin cell signaling, which leads to adaptive responses which ensure reproductive success.
There is extensive evidence that dopamine is a key neurotransmitter mediating maternal behavior. In addition, there is some evidence that serotonin may also be involved in regulating maternal behavior. Therefore, we hypothesised that the pheromonal-induced changes in maternal behavior would be associated with increased dopaminergic and/or serotonergic neuronal activity in the MPOA and other areas of the brain implicated in maternal behavior expression. Using HPLC to measure levels of dopamine and serotonin and their respective metabolites, we found a significant increase in serotonergic and dopaminergic neuronal activity in the MPOA of virgin female C57BL/6J mice after 24 hours of pheromonal contact. The neuronal activity returned to basal levels after exposure to pups. The data suggest that male mouse pheromones increase serotonergic and dopaminergic neuronal activity in the MPOA, but that dopamine and serotonin levels are tightly regulated within strict parameters dependent on what physical stimuli the female is receiving.
Changes in prolactin levels are associated with altered responses to anxiety. There is an increased risk of anxiety and depression with sustained periods of hyperprolactinemia, and in the postpartum period, where there are fluctuations in prolactin levels, there is an increased risk of mood disorders. As pheromones change both serum and brain prolactin levels and prolactin modulates anxiety, we hypothesised that female mice exposed to pheromones would show altered behavioral responses to a standardized test of anxiety. We found that male pheromone-exposed mice showed decreased levels of anxiety on an elevated plus maze compared to individually housed controls. Female mice exposed to female pheromones displayed 2 disparate responses to the plus maze. One female from each cage showed increased anxiety, while her cage-mate showed decreased anxiety, yet both groups of female mice showed impaired maternal behavior. We infer, that in this model, male pheromones decrease anxiety, but anxiety and expression of maternal behavior are not directly correlated.
The major signal transduction pathway activated by prolactin binding to its receptors in the brain is the JAK/STAT signalling pathway, and in some neurons, in particular, the STAT5B pathway. The expression of prolactin and its receptor affect maternal behavior in mice. Therefore, we hypothesised that if the JAK/STAT STAT5B pathway is involved in maternal behavior, then STAT5B-deficient mice would have altered maternal behavior. We found that there were no significant differences in expression of full maternal behavior between the STAT5B-deficient mice and wild-type controls. The data suggest that STAT5B is not required for normal expression of maternal behavior.
We propose that the prolactin-mediated pheromonal increase in neurogenesis, alteration in monoamine synthesis, and alteration of prolactin and prolactin receptor mRNA levels facilitate expression of enhanced maternal behavior. We further propose that the pheromonal decrease in anxiety does not mediate enhanced maternal behavior. In addition, we propose that prolactin does not mediate maternal behavior through STAT5B. While pheromones have previously been reported to exert powerful actions on the reproductive system, these results demonstrate for the first time that male pheromones potentially complement the prolactin-mediated establishment of maternal behavior.
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Wang, Ying. "Molecular and functional characterization of the prolactin receptor, prolactin-releasing peptide receptor, and growth hormone-releasing hormone receptor genes in chicken." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/HKUTO/record/B39556864.
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Hurst, Thomas Eugene. "Role of nociceptin/orphanin FQ in the prolactin, hypothalamic-pituitary-adrenal axis, and prolactin receptor response to acute stress in rats." Miami University Honors Theses / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=muhonors1303421079.
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Nguyen-Bresinsky, Dong Thi. "Immunopurification of Bovine Placental Lactogen." Fogler Library, University of Maine, 2005. http://www.library.umaine.edu/theses/pdf/Nguyen-Bresinsky2005.pdf.
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Almgren, Colleen Marie D. V. M. Ph D. "The potential role of potent prolactin antagonists as chemotherapeutics for human cancers: an evaluation of select prolactin antagonists in human breast cancer cells." The Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1104778150.
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Silveira, Marina Augusto. "Controle neuroendócrino da reprodução: fatores que modulam a atividade de neurônios GNRH e kisspetina." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/42/42131/tde-16112017-175827/.
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Neurônios GnRH e kisspeptina representam as populações neuronais de maior importância no controle da reprodução. Estradiol liga-se ao seu receptor expresso pelos neurônios kisspeptina para regular a libertação de GnRH. No modelo animal OVX+E a atividade do neurônio GnRH e pico de LH é depende do estradiol e hora do dia. Nesse estudo, embora a taxa de disparo dos neurônios GnRH seja similar entre os grupos, o padrão dos potenciais revelou uma mudança para maior duração do estouro em camundongos no proestrous, além do fato de uma maior resposta da hipófise. A prolactina tem grande impacto na modulação do eixo HPG e kisspeptina são mediadores dos efeitos da prolactina sobre a reprodução. Uma pequena porcentagem de neurônios de kisspeptina do AVPV foi indiretamente despolarizada pela prolactina. Este efeito requeria a via de sinalização PI3K. Camundongos portadores de inativação de Stat5a/b em células kisspeptina exibiram um início precoce de ciclicidade estro, indicando que os fatores de transcrição STAT5 exercem um efeito inibitório sobre o momento da puberdade.GnRH and kisspeptina neurons represent the most important neuronal populations in the control of reproduction. Estradiol binds to its receptor expressed by the kisspeptina neurons to regulate the release of GnRH. In the animal model OVX+E the activity of the GnRH neuron and LH surge is dependent of estradiol and time of day. In this study, although the firing rate of GnRH neurons was similar between groups, the pattern of potentials revealed a change to longer burst duration in mice in proestrous, and the pituitary response was greater in this group. Prolactin has impact on HPG axis modulation and kisspeptin is a mediator of the effects of prolactin on reproduction. A small percentage of AVPV kisspeptin neurons were indirectly depolarized by prolactin. This effect required the PI3K signaling pathway. Mice bearing Stat5a/b inactivation on kisspeptin cells exhibited an early onset of estrus cyclicity, indicating that STAT5 transcription factors exert an inhibitory effect on the time of puberty.
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Silva, Fábio Fernando Alves da. "Avaliação do papel de HSPB1 na modulação da autofagia induzida por PRL em células-beta." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-24082018-092045/.
Full textAbstract:
O diabetes mellitus tipo 1 é uma doença metabólica, caracterizada pela desregulação glicêmica, que ocorre devido a um ataque autoimune. A insulinoterapia é o tratamento clássico para o DM1. Contudo, alguns pacientes que apresentam essa doença não respondem de forma eficiente a este tratamento e apresentam episódios frequentes de hipoglicemia severa e despercebida (pacientes hiperlábeis). Essas complicações comprometem de forma significativa a qualidade de vida dessas pessoas. O transplante de ilhotas é uma importante alternativa para o tratamento de pacientes hiperlábeis com DM1. No entanto, essa terapia apresenta restrições como a necessidade de mais de um doador por transplante e significativa morte das ilhotas devido ao estresse provocado pelo procedimento de isolamento, além da morte promovida pelo sistema imune do paciente nos primeiros momentos pós-transplante. A autofagia é um mecanismo de reciclagem de componentes citoplasmáticos que é fundamental para a homeostase celular. Em condições de estresse, este mecanismo é ativado acima do seu nível basal, promovendo a degradação de agregados proteicos e organelas defeituosas, evitando assim, danos celulares que comprometam a viabilidade da célula. Trabalhos realizados por nosso grupo têm mostrado a citoproteção que PRL promove em células-beta, reduzindo a apoptose induzida por citocinas pró-inflamatórias. Também demonstramos o papel essencial de HSPB1 na inibição de apoptose induzida por PRL após o tratamento com citocinas. Além disso, resultados recentes de nosso laboratório mostraram um aumento nos níveis de autofagia em células-beta após sua exposição a citocinas, bem como uma restauração a níveis normais na presença de PRL. Visando um melhor entendimento do papel da PRL na modulação da autofagia em células-beta, o objetivo desse projeto foi estudar se HSPB1 também é essencial no mecanismo de regulação da autofagia induzido por PRL.Para tal, fizemos experimentos em modelos de células-beta MIN6, MIN6 silenciadas para HSPB1 (MIN6-shHSPB1) e MIN6 com sequencia short hairpin aleatória (MIN6- SsC), medindo a morte celular através de ensaios de viabilidade, e ensaios de western blot para avaliar os níveis de marcadores de autofagia e fluxo autofágico (degradação de autofagossomos), tratando as células com citocinas, prolactina e indutores ou inibidores de autofagia. Os resultados mostraram que a modulação da autofagia ocasionada pela prolactina em células-beta se dá, em parte, através de HSPB1. O tratamento com prolactina foi capaz de inibir a morte celular induzida por citocinas, mesmo na presença de cloroquina, um bloqueador de autofagia, o que nos levou a concluir que a autofagia não é uma via envolvida na citoproteção de células beta induzida por PRL. Os resultados gerados nesse estudo contribuíram para uma melhor compreensão dos eventos moleculares induzidos por PRL em células-beta, e poderão permitir a inferência de novas abordagens que melhorem a citoproteção, cultura e transplante dessas células em pacientes com diabetes tipo 1.Type 1 diabetes mellitus is a metabolic disease characterized by glycemic dysregulation, which occurs due to an autoimmune destruction of beta-cells. Insulin therapy is the gold standard treatment for DM1. However, some DM1 patients do not respond efficiently to this treatment and suffer frequent episodes of severe hypoglycemia unawareness. Since this complication jeopardizes the quality of life of these people, Islet transplantation is a therapeutic alternative indicated to treat these patients. However, besides the lack of enough organ donors, the loss of beta cells during both the isolation as well as the infusion of islets into the recipient induce a great estresse and thus a significant cell death is one of the drawbacks of this procedure. Autophagy is a mechanism of recycling cytoplasmic components and is essential for cellular homeostasis. Under estresse conditions, this mechanism is activated above basal levels, promoting the degradation of protein aggregates and defective organelles, thus avoiding cell damage that could compromise cell viability. Studies carried out by our group have shown not only that PRL promotes cytoprotection in beta-cells, reducing pro-inflammatory cytokines-induced apoptosis, but also that HSPB1 plays an essential role in this inhibition of apoptosis mediated by PRL after treatment with cytokines. Moreover, recent results from our laboratory showed an increase in autophagy levels in beta-cells after exposure to cytokines, as well as a restauration to normal levels in the presence of PRL. In order to better understand the role of PRL in the modulation of autophagy in these cells, the aim of this project is to study whether HSPB1 is also essential in the mechanism of autophagy regulation induced by PRL. Using MIN6 beta cell models where HSPB1 was silenced (MIN6-shHSPB1) or not (MIN6-SsC), we studied cell death by viability assays. Moreover, western blot assays were performed in order to assess levels of autophagy and autophagic flux markers in the cells.Our results showed that HSPB1 in one of the mediators of PRL-induced modulation of autophagy. Nevertheless, since hormonal treatment was still able to inhibit cytokinesinduced cell death even in the presence of chloroquin, an autophagy blocker, we conclude that autophagy is not a signaling pathway involved in PRl-induced beta-cell cytoprotection. Altogether, the results shown in this study may help to increase the knowledge of the molecular events induced by PRL in beta-cells, and may allow to infer new approaches to improve cytoprotection, culture and transplantation of these cells into type 1 diabetic patients.