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1

Lynch, Joseph Francis III. "Estrogenic Modulation of Fear Generalization." Kent State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1466095867.

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2

Morais, Samuel Rodrigues Lourenço de [UNESP]. "Influência da terapêutica hormonal estrogênica e do treinamento de força sobre o tecido muscular esquelético de ratas senis." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/144297.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
A diminuição das concentrações plasmáticas de estrógeno está intimamente relacionada com o aumento do estresse oxidativo e a diminuição da massa muscular em idosos. A terapêutica hormonal estrogênica (THE) e o treinamento de força (TF) apresentam resultados efetivos sobre a manutenção do tecido muscular em idosos. No entanto, os mecanismos responsáveis pelas melhorias induzias por ambas as intervenções são pouco elucidados. Nesse sentido, avaliamos os efeitos da THE, do TF e a associação sobre a manutenção do tecido muscular esquelético de ratas periestropausadas. Ratas Wistar (18 meses) foram distribuídas em: Grupo não treinado (NT-Veh), Grupo NT tratado com a THE (NT-E2), Grupo TF (TF-Veh) e Grupo TF-E2. Os animais receberam a THE (17β estradiol; 2 x semana; 25 µg/kg/administração) e/ou praticaram TF (3 x semana; 80% sobrecarga) durante 16 semanas. A THE e o TF induzem benefícios ao tecido muscular esquelético de ratas periestropausadas, no entanto, por diferentes maneiras. Enquanto a THE induziu diminuição do estresse oxidativo muscular (Dihidroetidina), o TF resultou em melhoras significativas na função muscular, no sistema antioxidante muscular (Catalase) e na expressão de miRNAs (206, 146b e 133a). Já a interação das intervenções resultou em melhora no estado redox (Sirt1, Sirt3, PGC-1α, COXIV), na responsividade dos receptores estrogênicos (ERα, ERβ e GPR30), e atividade de vias de sinalização do tecido muscular (IGF-1/Akt-1/mTOR). Além disso, as intervenções de maneira isolada ou em associação, levaram ao aumento no percentual de fibras glicolíticas e redução das oxidativas. Sugerimos que a aderências das intervenções (associadas ou não) possam minimizar/atenuar a perda da massa muscular observada em fases tardias durante o processo de envelhecimento.
The decrease of estrogen (E2) circulating levels is strongly related to increased oxidative stress and the loss of muscle mass in elderly. The hormone replacement therapy (HRT) and strength training (ST) are the main effective interventions to prevent the loss of muscle mass, however, the mechanisms involved in interventions-induced benefits are not well elucidated. In this sense we evaluate the effect of HRT, ST and association on skeletal muscle maintenance of periestropaused rats. Female Wistar rats (18 months old) were randomly assigned into: non-exercised and non-treated group (NE-Veh), NE treated group (NE-E2), exercised and non-treated group (ST-Veh) and ST-E2 group. The animals received the HRT (17β estradiol; 2 x week; 50 µg/kg/week) and/or performed ST (3 x week, 80% overload) for 16 weeks. The HRT and ST promoted beneficial effects on skeletal muscle of periestropaused rats, however, by different manners. While HRT treatment leaves the reduction of oxidative stress (Dihidroetidine), the ST resulted in significate improvement on skeletal muscle function, in skeletal muscle antioxidant system (Catalase) and in miRNAs expression (2016, 146b and 133a). Already, the association of interventions resulted in improvement of redox state (Sirt1, Sirt3, PGC-1α, COXIV), in estrogen receptor responsiveness (ERα, ERβ and GPR30) and the activity of skeletal muscle signaling pathways (IGF-1/Akt-1/mTOR). In addition, the interventions, isolated or combinated, leaves an increase of the percentage of glycolytic fibers and reduced percentage of oxidative fibers. We suggest that the adherence to interventions (combinated or not) could minimize/attenuate the loss of skeletal muscle mass observed in later phases of aging process.
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3

Devergne, Jimmy. "Approche multi-stress : impact du changement climatique et d'un stress chimique (perturbateur endocrinien) sur le cycle de vie complet d'un poisson sentinelle marin." Electronic Thesis or Diss., Brest, 2024. http://theses-scd.univ-brest.fr/2024/These-2024-SML-Biologie_biochimie_cellulaire_et_moleculaire-DEVERGNE_Jimmy.pdf.

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Les travaux présentés dans cette thèse proposent d’évaluer l'impact d’un stress oestrogénique, durant des phases clés du cycle de vie des poissons (développement précoce et gamétogénèse), dans un contexte de changement global, tel que simulé par le scénario RCP8.5 du GIEC à l'horizon 2100 (+3 °C et -0.4 unité pH). Elle s’appuie sur une expérimentation en milieu contrôlé menée sur l’épinoche à trois épines (Gasterosteus aculeatus), permettant d’une part, l'exposition à des scénarios climatiques différents (actuel et RCP8.5) sur tout le cycle de vie de cette espèce et d’autre part, de combiner ce stress climatique à un stress oestrogénique (17α-ethynylestradiol = EE2 ; 15 ng.l-1) pendant les stades embryo-larvaires et en fin de gamétogénèse. L’impact du stress climatique, ou du multi-stress, a été abordé par une approche intégrative, s'appuyant sur des analyses physiologiques, biochimiques et moléculaires, permettant d’observer les effets sur la croissance, la reproduction et la survie à différents niveaux biologiques. En résumé, cette étude montre que des conditions de températures plus élevées et de pH plus bas augmentent les coûts métaboliques, affectant la croissance des juvéniles. Cet effet sur la croissance est accentué lors d’une contamination précoce à l’EE2. Au stade adulte, les coûts métaboliques générés par le stress climatique, impactent la maturité sexuelle et le succès reproducteur (diminution du nombre de femelles capables de se reproduire, retard et réduction de la période de ponte, maturation ovocytaire et qualité des oeufs amoindries). Ces effets ne sont pas modulés par le stress oestrogénique supplémentaire, appliqué en fin de gamétogénèse. Toutefois, la contamination pendant les stades précoces a entraîné des effets durables, comme une féminisation des mâles et une perturbation de l'axe de la reproduction, sans modulation par la condition climatique. Enfin, les deux principaux résultats sur la survie concernent, deux périodes : 1- En condition de stress climatique, un pic de mortalité a été observé après la reproduction, associé à la prolifération de Vibrio rotiferianus et à un état physiologique plus vulnérable des épinoches en période de post-reproduction et de températures plus élevées. 2- En condition de multistress où une mortalité totale des larves issues de parents contaminés à l’EE2 a été constatée suggérant un rôle crucial de l’exposition des géniteurs sur les réponses de la descendance. Ces travaux soulignent l’intérêt de considérer le multi-stress sur l’entièreté du cycle de vie pour estimer la vulnérabilité des espèces aquatiques dans un environnement futur
The work presented in this thesis aims to evaluate the effects of estrogenic stress during key phases of the fish life cycle (early development and gametogenesis) in the context of global change as simulated by the IPCC RCP8.5 scenario for the year 2100 (+3 °C and -0.4 pH units). It is based on a controlled environment experiment carried out on the three-spined stickleback (Gasterosteus aculeatus), which allows exposure to different climate scenarios (current and RCP8.5) throughout the life cycle of this species and, in addition, to combine this climatic stress with estrogenic stress (17α-ethynylestradiol = EE2 ; 15 ng.l-1) during the embryonic-larval stages and at the end of gametogenesis. The effects of climatic stress, or multistress, were addressed by an integrative approach based on physiological, biochemical and molecular analyses, allowing the observation of effects on growth, reproduction and survival at different biological levels. In conclusion, this study shows that higher temperature and lower pH conditions increase metabolic costs and thus affect juvenile growth. This effect on growth is exacerbated by early contamination with EE2. At the adult stage, the metabolic costs generated by climatic stress affect sexual maturity and reproductive success (reduction in the number of reproductive females, delay and reduction in the spawning period, impaired oocyte maturation and egg quality). These effects are not modulated by additional estrogenic stress applied at the end of gametogenesis. On the other hand, contamination during early stages resulted in permanent effects such as feminisation of males and disruption of the reproductive axis, without modulation by climatic conditions. Finally, the two main results on survival concern two periods: 1- Under climatic stress conditions, a post-reproductive mortality peak wasobserved, associated with the proliferation of Vibrio rotiferianus and a more vulnerable physiological state of the sticklebacks during the post-reproductive period and at higher temperatures. 2- Under multistress conditions, a total mortality of larvae from EE2-contaminated parents was observed, suggesting a critical role of parental exposure on offspring responses. This work highlights the importance of considering multi-stress throughout the life cycle to assess the vulnerability of aquatic species in a future environment
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4

Rubinow, Katya. "Differential Endogenous Estrogen Exposure Influences Prefrontal Cortex Response to Acute Stress." Yale University, 2006. http://ymtdl.med.yale.edu/theses/available/etd-06282006-142135/.

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The present study was conducted to determine the effect of differential endogenous estrogen exposure in rats on stress-induced changes in spatial working memory. Subjects comprised male (n=8) and female (n=10) Sprague-Dawley rats, which were trained to complete a T maze, delayed alternation task. Performance was scored as a percentage of trials during which the correct maze arm was selected. Subjects scores were recorded after 1 and 2 hours of restraint stress, as well as after 1 hour of unimpeded movement in a cage placed in the testing room. Restraint stress was effected through physical confinement within plastic, cylindrical tubing. Female subjects underwent each of the testing conditions twice, during periods of high and low endogenous estrogen exposure, as ascertained by microscopic examination of vaginal epithelial cells for estrous cycle stage determination. Females in proestrus (elevated endogenous estrogen exposure) subjected to 1 hour of restraint performed significantly worse than their baseline scores (p=0.0017) or females in estrus (low endogenous estrogen exposure) after 1 hour of restraint (p=0.00014). After 1 hour of restraint, females in proestrus also committed an increased rate of perseverative errors compared to females in estrus, although this increase did not achieve statistical significance (p=0.06). No appreciable differences existed among subject groups in baseline performance or subsequent to 2 hours of restraint stress. Resultant data indicate impaired working memory among female rats under conditions of stress in the context of elevated endogenous estrogen exposure. This study, then, suggests a potential synergistic effect of stress and estrogen in compromising prefrontal cortex function and, therefore, may lend insight into the observed sex-related disparity in the incidence of major depressive disorder and other anxiety-related mood disorders.
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5

Bokov, Alex F. "The role of somatotropic and estrogen signaling in longevity and resistance to oxidative stress a dissertation /." San Antonio : UTHSC, 2008. http://proquest.umi.com.libproxy.uthscsa.edu/pqdweb?did=1588777011&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.

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6

Santos, Elba LÃcia Wanderley dos. "Efeitos da Acupuntura, Eletroacupuntura e Metformina Sobre o Estresse Oxidativo, InflamaÃÃo e Glicemia em Ratas Sadias Submetidas a EstÃmulo EstrogÃnico." Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=9040.

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CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior
O desempenho fisiolÃgico da atividade celular requer um equilÃbrio entre a produÃÃo de espÃcies de radicais livres e a sua desativaÃÃo por agentes reguladores e protetores. Quando esse equilÃbrio à quebrado, surge o estresse oxidativo. Diversos estudos experimentais utilizando estrÃgenos para a induÃÃo de distÃrbios ovarianos e metabÃlicos, com destaque para a SÃndrome dos OvÃrios PolicÃsticos (SOP), estÃo disponÃveis na literatura cientÃfica. A Metformina (MTF) à um anti-hiperglicemiante, frequentemente utilizado para tratamento da SOP, permitindo a restauraÃÃo da ciclicidade menstrual, induÃÃo da ovulaÃÃo e o aumento da ocorrÃncia de gestaÃÃo. Na Medicina Tradicional Chinesa, a Acupuntura (Ac) e a Eletroacupuntura (EAc) sÃo utilizadas na promoÃÃo do equilÃbrio orgÃnico, mediante estÃmulo de vias nervosas produtoras de neurotransmissores especÃficos, resultando em uma resposta anti-inflamatÃria, analgÃsica e reguladora autonÃmica. Neste estudo, objetivou-se avaliar os efeitos da MTF, da Ac e da EAc aplicadas nos acupontos Zusanli (E36) e Sanyjiao (BP6), sobre o estresse oxidativo sistÃmico e local, inflamaÃÃo e glicemia em ratas sadias submetidas a estÃmulo estrogÃnico. No experimento, 42 ratas foram distribuÃdas aleatoriamente em sete grupos. Em 30 ratas (grupos G1C+, G2M, G3Ac, G4EAc2, G5EAc100) administrou-se estrogÃnio (valerato de estradiol, 4mg, dose Ãnica). Os dois grupos restantes serviram como controles negativos (G6M, G7) e nÃo receberam estÃmulo estrogÃnico. ApÃs 60 dias, iniciou-se a segunda fase do estudo, compreendendo um perÃodo de dez dias. A Ac e EAc (2/100Hz), foram aplicadas, sob anestesia, em dias alternados, por 20 minutos, durante nove dias nos grupos G3Ac, G4EAc2, G5EAc100; MTF foi administrada diariamente, por gavagem, durante nove dias aos grupos G2M e G6M. No 10 dia desta fase, todas as ratas foram submetidas ao teste de tolerÃncia oral a glicose,e avaliadas em trÃs ocasiÃes: antes do inicio do teste e apÃs 60/120 minutos; seguiu-se a laparotomia, sob anestesia, para coleta de sangue na artÃria aorta abdominal e exÃrese do Ãtero e ovÃrios para exames a seguir: dosagem de SubstÃncias Reativas ao Ãcido TiobarbitÃrico (TBARs), da Glutationa (GSH) reduzida, da Mieloperoxidase (MPO) e da histopatologia ovariana. Os resultados mostraram um aumento significativo das concentraÃÃes plasmÃticas de GSH nos grupos G3Ac, G4EAc2 e G5EAc100 comparados ao G1 (24,50Â1,59 vs 20,30Â0,43, p<0,05; 30,80Â3,22 e 40,30Â3,48 vs 20,30Â0,43, p<0,0001), respectivamente. Houve aumento significante das concentraÃÃes de GSH no tecido ovariano das ratas tratadas com EAc2/100 (47,00Â17,60 vs 25,70Â2,33, p<0,05 e 63,00Â12,40 vs 25,70Â2,33, p<0,0001). A EAc2/100 promoveu aumento significante nas concentraÃÃes plasmÃticas de TBARS (0,231 0,09 vs 0,054Â0,07, p<0,05 e 0,296Â0,09 vs 0,054Â0,07, p<0,001). Houve reduÃÃo significante na atividade da MPO ovariana nos grupos G4EAc2 e G5EAc100 (0,59Â0,21 vs 1,76Â0,31, p<0,05 e 0,65Â0,05 vs 1,76Â0,31, p<0,0001). A administraÃÃo de MTF nÃo promoveu alteraÃÃes nos marcadores oxidativos ou inflamatÃrios. NÃo mostrou alteraÃÃo da glicemia em nenhum dos grupos estudados. No estudo do nÃmero de folÃculos, corpos lÃteos e cistos foliculares nÃo houve diferenÃa significativa entre todos os grupos estudados, ao exame histopatolÃgico. Conclui-se que a aplicaÃÃo de EAc2/100Hz promove proteÃÃo local e sistÃmica sobre o estresse oxidativo por aumento das concentraÃÃes de GSH, alÃm de reduzir o estado inflamatÃrio no ovÃrio de ratas sadias submetidas a estimulo estrogÃnico.
O desempenho fisiolÃgico da atividade celular requer um equilÃbrio entre a produÃÃo de espÃcies de radicais livres e a sua desativaÃÃo por agentes reguladores e protetores. Quando esse equilÃbrio à quebrado, surge o estresse oxidativo. Diversos estudos experimentais utilizando estrÃgenos para a induÃÃo de distÃrbios ovarianos e metabÃlicos, com destaque para a SÃndrome dos OvÃrios PolicÃsticos (SOP), estÃo disponÃveis na literatura cientÃfica. A Metformina (MTF) à um anti-hiperglicemiante, frequentemente utilizado para tratamento da SOP, permitindo a restauraÃÃo da ciclicidade menstrual, induÃÃo da ovulaÃÃo e o aumento da ocorrÃncia de gestaÃÃo. Na Medicina Tradicional Chinesa, a Acupuntura (Ac) e a Eletroacupuntura (EAc) sÃo utilizadas na promoÃÃo do equilÃbrio orgÃnico, mediante estÃmulo de vias nervosas produtoras de neurotransmissores especÃficos, resultando em uma resposta anti-inflamatÃria, analgÃsica e reguladora autonÃmica. Neste estudo, objetivou-se avaliar os efeitos da MTF, da Ac e da EAc aplicadas nos acupontos Zusanli (E36) e Sanyjiao (BP6), sobre o estresse oxidativo sistÃmico e local, inflamaÃÃo e glicemia em ratas sadias submetidas a estÃmulo estrogÃnico. No experimento, 42 ratas foram distribuÃdas aleatoriamente em sete grupos. Em 30 ratas (grupos G1C+, G2M, G3Ac, G4EAc2, G5EAc100) administrou-se estrogÃnio (valerato de estradiol, 4mg, dose Ãnica). Os dois grupos restantes serviram como controles negativos (G6M, G7) e nÃo receberam estÃmulo estrogÃnico. ApÃs 60 dias, iniciou-se a segunda fase do estudo, compreendendo um perÃodo de dez dias. A Ac e EAc (2/100Hz), foram aplicadas, sob anestesia, em dias alternados, por 20 minutos, durante nove dias nos grupos G3Ac, G4EAc2, G5EAc100; MTF foi administrada diariamente, por gavagem, durante nove dias aos grupos G2M e G6M. No 10 dia desta fase, todas as ratas foram submetidas ao teste de tolerÃncia oral a glicose,e avaliadas em trÃs ocasiÃes: antes do inicio do teste e apÃs 60/120 minutos; seguiu-se a laparotomia, sob anestesia, para coleta de sangue na artÃria aorta abdominal e exÃrese do Ãtero e ovÃrios para exames a seguir: dosagem de SubstÃncias Reativas ao Ãcido TiobarbitÃrico (TBARs), da Glutationa (GSH) reduzida, da Mieloperoxidase (MPO) e da histopatologia ovariana. Os resultados mostraram um aumento significativo das concentraÃÃes plasmÃticas de GSH nos grupos G3Ac, G4EAc2 e G5EAc100 comparados ao G1 (24,50Â1,59 vs 20,30Â0,43, p<0,05; 30,80Â3,22 e 40,30Â3,48 vs 20,30Â0,43, p<0,0001), respectivamente. Houve aumento significante das concentraÃÃes de GSH no tecido ovariano das ratas tratadas com EAc2/100 (47,00Â17,60 vs 25,70Â2,33, p<0,05 e 63,00Â12,40 vs 25,70Â2,33, p<0,0001). A EAc2/100 promoveu aumento significante nas concentraÃÃes plasmÃticas de TBARS (0,231 0,09 vs 0,054Â0,07, p<0,05 e 0,296Â0,09 vs 0,054Â0,07, p<0,001). Houve reduÃÃo significante na atividade da MPO ovariana nos grupos G4EAc2 e G5EAc100 (0,59Â0,21 vs 1,76Â0,31, p<0,05 e 0,65Â0,05 vs 1,76Â0,31, p<0,0001). A administraÃÃo de MTF nÃo promoveu alteraÃÃes nos marcadores oxidativos ou inflamatÃrios. NÃo mostrou alteraÃÃo da glicemia em nenhum dos grupos estudados. No estudo do nÃmero de folÃculos, corpos lÃteos e cistos foliculares nÃo houve diferenÃa significativa entre todos os grupos estudados, ao exame histopatolÃgico. Conclui-se que a aplicaÃÃo de EAc2/100Hz promove proteÃÃo local e sistÃmica sobre o estresse oxidativo por aumento das concentraÃÃes de GSH, alÃm de reduzir o estado inflamatÃrio no ovÃrio de ratas sadias submetidas a estimulo estrogÃnico.
The physiological performance of cellular activity requires a balance between the production of free radicals and their deactivation by regulators and surge protectors. When this balance is broken, the oxidative stress takes place. Several experimental studies using estrogens to induction of ovarian and metabolic disorders, with emphasis on the polycystic ovary syndrome (PCOS), are available in the scientific literature.The Metformin (MTF) is a medication used for diabetic patients, and is often used for treatment of Polycystic Ovary Syndrome (PCOS), allowing restoration of cyclicality, induction of ovulation and menstruation. Acupuncture (Ac) and Electroacupuncture (EAc) are used in Traditional Chinese Medicine for the promotion of organic equilibrium, through stimulation of nerve pathways producing specific neurotransmitters, resulting in an antinflammatory, analgesic and autonomic regulatory response.This study aimed at evaluating the effects of MTF and Ac and EAc, applied on Zusanli (E36) and Sanyjiao (BP6) acupoints on the local and systemic oxidative stress, inflammation and blood glucose levels in healthy rats submitted to estrogenic stimulation. In the experiment, 42 rats were distributed randomly assigned into seven groups. In the experiment, 42 rats were randomly assigned into seven groups. Thirty rats (groups G1C , G2M, G3Ac, G4EAc2, G5EAc100) were administered estrogen (estradiol valerate, 4mg, single dose). The two remaining groups served as negative controls (G6M, G7) and received no estrogenic stimulation. After 60 days, began the second phase of the study, comprising a ten-day period. Ac and EAc (2/100Hz), were applied for 20 minutes, under anesthesia, in alternated days during nine days, to groups G3Ac, G4EAc2, and G5EAc100. MTF was given daily during nine days by gavage to G2M and G6M groups. On the 10th day, all rats were subjected to the oral glucose tolerance test, and evaluated on three occasions: before the beginning of the test and after 60/120 minutes. Next, followed laparotomy, under anesthesia, for collection of blood from the abdominal aorta artery and harvesting of uterus and ovary for examination. Parameters analysed included the Thiobarbituric Acid Reactive Substances (TBARS), reduced Glutathione (GSH), Myeloperoxidase (MPO), and ovarian histopathology. At the end of the experiment plasma concentrations of GSH increased significantly in G3Ac, G4EAc2 and G5EAc100 groups compared to G1 (24.50Â1.59 vs 20.30Â0.43, p<0.05; 30.80Â3.22 and 40.30Â3.48 vs 20.30Â0.43, p<0.0001) respectively. There has been a significant increase in concentrations of GSH in ovarian tissue of rats treated with EAc2/100 (47.00Â17.60 vs 25.70Â2.33, p<.005 and 63.00Â12,40 vs 25,70Â2.33, p<0.0001). There was a significant reduction in ovarian MPO activity in groups G4EAc2 and G5EAc100 (0.59Â0.21 vs 1.76Â0.31, p<0.05 and 0.65Â0.05 vs 1.76Â0.31p<0.001). MTF did not promote changes in oxidative or inflammatory markers. There was no change in blood glucose levels in any of the groups studied. Corpus luteum and follicular cysts number were not different in all groups. It is concluded that EAc2/100Hz treatments promote systemic and local protection on oxidative stress by increasing GSH concentrations and by reducing the inflammatory status in the ovary of healthy rats submitted to estrogenic stimulation.
The physiological performance of cellular activity requires a balance between the production of free radicals and their deactivation by regulators and surge protectors. When this balance is broken, the oxidative stress takes place. Several experimental studies using estrogens to induction of ovarian and metabolic disorders, with emphasis on the polycystic ovary syndrome (PCOS), are available in the scientific literature.The Metformin (MTF) is a medication used for diabetic patients, and is often used for treatment of Polycystic Ovary Syndrome (PCOS), allowing restoration of cyclicality, induction of ovulation and menstruation. Acupuncture (Ac) and Electroacupuncture (EAc) are used in Traditional Chinese Medicine for the promotion of organic equilibrium, through stimulation of nerve pathways producing specific neurotransmitters, resulting in an antinflammatory, analgesic and autonomic regulatory response.This study aimed at evaluating the effects of MTF and Ac and EAc, applied on Zusanli (E36) and Sanyjiao (BP6) acupoints on the local and systemic oxidative stress, inflammation and blood glucose levels in healthy rats submitted to estrogenic stimulation. In the experiment, 42 rats were distributed randomly assigned into seven groups. In the experiment, 42 rats were randomly assigned into seven groups. Thirty rats (groups G1C , G2M, G3Ac, G4EAc2, G5EAc100) were administered estrogen (estradiol valerate, 4mg, single dose). The two remaining groups served as negative controls (G6M, G7) and received no estrogenic stimulation. After 60 days, began the second phase of the study, comprising a ten-day period. Ac and EAc (2/100Hz), were applied for 20 minutes, under anesthesia, in alternated days during nine days, to groups G3Ac, G4EAc2, and G5EAc100. MTF was given daily during nine days by gavage to G2M and G6M groups. On the 10th day, all rats were subjected to the oral glucose tolerance test, and evaluated on three occasions: before the beginning of the test and after 60/120 minutes. Next, followed laparotomy, under anesthesia, for collection of blood from the abdominal aorta artery and harvesting of uterus and ovary for examination. Parameters analysed included the Thiobarbituric Acid Reactive Substances (TBARS), reduced Glutathione (GSH), Myeloperoxidase (MPO), and ovarian histopathology. At the end of the experiment plasma concentrations of GSH increased significantly in G3Ac, G4EAc2 and G5EAc100 groups compared to G1 (24.50Â1.59 vs 20.30Â0.43, p<0.05; 30.80Â3.22 and 40.30Â3.48 vs 20.30Â0.43, p<0.0001) respectively. There has been a significant increase in concentrations of GSH in ovarian tissue of rats treated with EAc2/100 (47.00Â17.60 vs 25.70Â2.33, p<.005 and 63.00Â12,40 vs 25,70Â2.33, p<0.0001). There was a significant reduction in ovarian MPO activity in groups G4EAc2 and G5EAc100 (0.59Â0.21 vs 1.76Â0.31, p<0.05 and 0.65Â0.05 vs 1.76Â0.31p<0.001). MTF did not promote changes in oxidative or inflammatory markers. There was no change in blood glucose levels in any of the groups studied. Corpus luteum and follicular cysts number were not different in all groups. It is concluded that EAc2/100Hz treatments promote systemic and local protection on oxidative stress by increasing GSH concentrations and by reducing the inflammatory status in the ovary of healthy rats submitted to estrogenic stimulation.
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Filho, Procópio Cleber Gama de Barcellos. "Efeitos da corticosterona e do estrógeno na atividade do eixo HPA de ratas: comportamento e comprimento dos telômeros." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/17/17134/tde-13092018-141304/.

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O estresse crônico promove diversas alterações no funcionamento de um organismo. O aumento de glicocorticoides pode interferir no estado físico e psicológico de um individuo. Trabalhos recentes correlacionam estresse psicossocial crônico à redução do comprimento dos telômeros de determinadas células. E o estrógeno, além de ser um fator modulador da atividade do sistema de estresse, também pode interferir no comprimento dos telômeros. O objetivo desse trabalho foi verificar se a exposição crônica aos glicocorticóides promove alterações no comprimento dos telômeros de áreas encefálicas envolvidas no controle da atividade do eixo Hipotálamo-Hipófise-Adrenal (HPA) e em respostas comportamentais de ratas, e se o estrógeno pode modular essas alterações. Ratas Wistar ovariectomizadas foram tratadas com cipionato de estradiol (50 ou 100 µg/kg, s.c.) ou óleo, e submetidas à administração de corticosterona 20 mg/Kg ou veículo (salina isotônica 2% Tween 80, s.c.), durante 28 dias. No 25 º dia os animais foram submetidos ao teste do nado forçado, e no 27º dia, ao teste de labirinto em cruz elevado. No dia subsequente ao término do tratamento hormonal, os animais foram eutanasiados para coleta do sangue, cérebro e hipófise. O tratamento com cipionato de estradiol causou: aumento das concentrações plasmáticas de corticosterona e progesterona; redução da expressão de mRNA para CRH, AVP e POMC no PVN; um efeito ansiolítico a avaliado pelo teste do labirinto em cruz elevado; . um efeito depressivo indicado pelo teste de nado forçado; reduziu o tamanho dos na amígdala central e hipocampo dorsal, mas não no PVN. A corticosterona causou: redução da secreção de gonadotrofina; redução da expressão de RNA mensageiro para CRH e POMC e aumento para AVP no PVN; um efeito depressivo indicado pelo teste de nado forçado. O conjunto de resultados mostra que modificação na atividade do eixo HPA e a variação das concentrações plasmáticas de estrógeno podem provocar diversas alterações de ações hormonais, atividades comportamentais e de estrutura do DNA em áreas cerebrais.
Chronic stress promotes several changes in the functioning of an organism. Increased glucocorticoids may interfere with an individual\'s physical and psychological state. Recent works correlate chronic psychosocial stress to the reduction of the telomere length of certain cells. And estrogen, besides being a modulating factor of the activity of the stress system, can also interfere in the length of telomeres. The objective of this study was to verify if chronic exposure to glucocorticoids promotes changes in telomere length of encephalic areas involved in the control of hypothalamic-hypophysis-adrenal (HPA) axis activity and in rat behavioral responses, and whether estrogen can modulate these changes. Ovariectomized Wistar rats were treated with estradiol cypionate (50 or 100 ?g / kg, s.c.) or oil, and given 20 mg / kg corticosterone or vehicle (isotonic saline 2% Tween 80, s.c.) for 28 days. On the 25th day the animals were submitted to the forced swim test, and on the 27th day, the elevated plus maze test. On the day after the end of the hormonal treatment, the animals were euthanized for collection of blood, brain and pituitary gland. Treatment with estradiol cypionate caused: increased corticosterone and progesterone plasma concentrations; reduction of mRNA expression for CRH, AVP and POMC in PVN; an anxiolytic effect as assessed by the elevated plus maze test. A depressive effect indicated by the forced swim test; reduced size in the central amygdala and dorsal hippocampus, but not in PVN. Corticosterone caused: reduction of gonadotrophin secretion; reduction of mRNA expression for CRH and POMC and increase for AVP in PVN; a depressive effect indicated by the forced swim test. The set of results shows that changes in HPA axis activity and variation in plasma estrogen concentrations can lead to several changes in hormonal actions, behavioral activities and DNA structure in brain areas.
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Franco, Lucas Augusto Moysés. "Efeito da proteção desencadeada pelo estrógeno na linhagem C6 de glioma de rato." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-16082011-093651/.

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Evidências sugerem que as células da glia desempenham um papel importante na sinalização neuronal e na resposta inflamatória no Sistema Nervoso Central (SNC). Respostas inflamatórias crônicas, bem como a ativação da glia estão associadas com doenças neurodegenerativas, como Parkinson e Alzheimer. A inflamação crônica pode ser modulada por altas concentrações de espécies reativas de oxigênio (ERO) que potencializam esse quadro. O estrógeno (E2) é bem conhecido por suas ações neuroprotetoras que podem ser exercidas via receptores clássicos (ESR1, ESR2), não-classicos (GPER-1) ou ainda por sua ação antioxidante, proveniente da alta semelhança com as moléculas dos flavonóides. A ação do E2 no SNC é relevante uma vez que este hormônio está relacionado com a modulação da memória, neurogênese e plasticidade. Este trabalho tem como objetivo investigar o papel protetor do E2 em linhagem de células C6 de glioma de ratos em um modelo de estresse oxidativo que induz morte celular pela exposição a concentrações tóxicas de peróxido de hidrogênio (H2O2). Ensaios de PCR, Western Blot e de imunofluorescência confirmaram a presença e funcionalidade dos receptores ESR1, enquanto ensaios de PCR mostraram a presença do RNAm para o GPER-1 em células C6. Nossos resultados confirmaram que a H2O2 induz morte nas células C6 e o pré-tratamento com E2 (por 24 horas) e G1 (por 20 minutos) diminuiu a toxicidade da H2O2 de maneira dose-dependente, gerando aumento de viabilidade celular. Estes resultados destacam o envolvimento do E2 e seus receptores na prevenção do dano celular em células da glia. Além disso, eles também sugerem que o rápido efeito protetor do E2 parece estar associado com a sinalização rápida do E2 via GPER-1. Por Western blot e RT-PCR avaliamos a participação da via AKT-CREBBDNF frente aos tratamentos com E2, moduladores seletivos de estrógeno (SERMs) e G1, onde observamos que estes são capazes de modular a expressão da proteína AKT e os níveis de RNAm para BDNF.
Evidence suggests that glial cells play an important role in neuronal signaling and inflammatory responses in the central nervous system (CNS). Chronic inflammatory responses, as well as activation of glia, are associated with neurodegenerative disorders such as Parkinson´s and Alzheimer´s diseases. Chronic inflammation can be modulated by high concentrations of reactive oxygen species (ROS) that enhance this process. Estrogen (E2) is well known for its neuroprotective actions that can be performed via classical (ESR1, ESR2) and non-classical receptors (GPER-1) or by its antioxidant action due to its high similarity to flavonoids molecules. E2 action in the CNS is relevant as this hormone is associated to memory modulation, neurogenesis and plasticity. This work has as purpose to investigate the protective role of E2 in rat C6 glioma cell lines in a model of oxidative stress that induces cell death by exposure to toxic concentrations of hydrogen peroxide (H2O2). PCR, Western blot and immunofluorescence assays have confirmed the presence and functionality of the ESR1 receptor, while PCR assay has showed the presence of GPER-1 receptor mRNA in C6 cells. Our results confirmed that H2O2 induces cell death and pre-treatment with E2 (24 hours) and G1 (20 minutes) reduces H2O2 toxicity in a dose-dependent way, leading to increased cell viability. These results highlight the involvement of E2 and its receptors in preventing cell damage in glial cells. Moreover, they also suggest that the prompt E2 protective effect seems to be associated to the fast E2 signaling via GPER-1. We also evaluated the involvement of AKT-CREB-BDNF pathway when C6 cells were treated with E2, selective estrogen modulators (SERMs) and G1 by Western blot and RT-PCR assays, and we could notice that they can modulate the expression of AKT protein and BDNF RNAm levels.
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Thomas-Ahner, Jennifer Marie. "Gender differences in UVB induced cutaneous inflammation and skin carcinogenesis." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1179949864.

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Wu, Wing Man. "An investigation into the neuroprotective effects of estrogen and progesterone in a model of homocysteine-induced neurodegeration." Thesis, Rhodes University, 2006. http://hdl.handle.net/10962/d1003284.

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Homocysteine (Hcy) is a sulfur containing amino acid and is a potent neurotoxin. It has been shown that elevated levels of Hcy, termed hyperhomocysteinemia, plays a role in the pathologies of Alzheimer’s disease (AD) and age-related cognitive decline. Hcy is a glutamate agonist, which causes in increase in Ca[superscript (2+)] influx via the activation of NMDA class of excitatory amino acid receptors, which results in neuronal cell death and apoptosis. Estrogen and progesterone are female hormones that are responsible for reproduction and maternal behaviour. However, in the last decade, it is evident that both female hormones have neuroprotective properties in many animal models of neurodegeneration. Collectively, both estrogen and progesterone reduce the consequences of the oxidative stress by enhancing the antioxidant defence mechanisms, reducing excitotoxicity by altering glutamate receptor activity and reducing the damage caused by lipid peroxidation. However, the mechanisms by which estrogen and progesterone provide such neuroprotection probably depend on the type and concentration of hormone present. Moreover, numerous studies have shown that hormone replacement therapy (HRT, estrogen and progestins) or estrogen-only replacement therapy (ERT) may prevent or delay the onset of AD and improve cognition for women with AD. Clinical trials have also shown that women taking HRT may modify the effects of Hcy levels on cognitive functioning. Oxidative stress increases in the aging brain and thus has a powerful effect on enhanced susceptibility to neurodegenerative disease. The detection and measurement of lipid peroxidation and superoxide anion radicals in the brain tissue supports the involvement of free radical reactions in neurotoxicity and in neurodegenerative disorders. The hippocampus is an important region of the brain responsible for the formation of memory. However, agents that induce stress in this area have harmful effects and could lead to dementia. This study aims to investigate and clarify the neuroprotective effects of estrogen and progesterone, using Hcy-induced neurodegenerative models. The initial studies demonstrate that estrogen and progesterone have the ability to scavenge potent free radicals. Histological studies undertaken reveal that both estrogen and progesterone protect against Hcy-induced neuronal cell death. In addition, immunohistochemical investigations show that Hcy-induced apoptosis in the hippocampus can be inhibited by both estrogen and progesterone. However, estrogen also acts at the NMDA receptor as an agonist, while progesterone blocks at the NMDA receptor. These mechanisms reduce the ability of Hcy to cause damage to neurons, since Hcy-induced neurotoxicity is dependent on the overstimulation of the NMDA receptor. SOD and GPx are important enzymatic antioxidants which can react with ROS and neutralize them before these inflict damage in the brain. Hcy can increase oxidative stress by inhibiting expression and function of these antioxidants. However, it has been shown that the antioxidant abilities of both estrogen and progesterone can up-regulate the activities of SOD and GPx. These results provide further evidence that estrogen and progesterone act as antioxidants and are free radical scavengers. The discovery of neuroprotective agents is becoming important as accumulating evidence indicates the protective role of both estrogen and progesterone in Hcy-induced neurodegeneration. Thus further work in clinical trials is needed to examine whether reducing Hcy levels with HRT can become the treatment of neurodegenerative disorders, such as Alzheimer’s disease.
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SOUSA, Shirley Maria de. "Efeito a curto e longo prazo da restrição proteica perinatal no tronco encefálico de fêmeas." Universidade Federal de Pernambuco, 2016. https://repositorio.ufpe.br/handle/123456789/18021.

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CNPq
Durante o período reprodutivo,fêmeasproduzemelevados níveis deestrogênios.Os três principais sãoestrona (E1), 17-β-estradiol (E2) e o estriol (E3).O 17-β-estradiol é o estrogênio predominante durante os anos reprodutivos tanto em termos de níveis séricos absolutos como em termos de atividade estrogênica. Inúmeros relatos na literatura postulam que os estrogênios apresentam um importante papel cardioprotetor, e que essa ação protetora pode ocorrer tanto por expressão de genes como também pela ativação de proteínas de cascata de sinalização que culmina no efeito protetor dos estrogênios. Entretanto, o papel dos estrogênios no tecido cerebralcombatendo o estresse oxidativo ainda não é totalmente compreendido. No tronco encefálico, neurônio localizado especificamente na região do bulbo tem um importante papel no controle neuronal do sistema cardiovascular, pois atuam tanto no controle da atividade simpática como também na recepção dos sinais químicos e mecânicos provenientes de barorreceptores e quimiorreceptores. Em adição a essa rede neuronal do controle simpático e da decodificação de sinais aferentes, o tronco encefálico esta sob a influência das ações das espécies reativas de oxigênio-EROS, moléculas essas que tem alta capacidade de induzir a oxidação de lipídios de membrana, proteínas ou mesmo ao DNA, podendo levar a um quadro definido por estresse oxidativo. Hoje em dia, o estresse oxidativo é considerado um dos principais causadores de doenças neurológicas, tais como Parkinson, Alzheimer, Esclerose lateral amiotrófica entre outras. Dessa forma, o objetivo dessarevisãofoiinvestigar os efeitos neuromodulador dosestrogênios na prole fêmeas de mães que foram submetidas adesnutrição proteica no período perinatal (gestação e lactação).
During the reproductive age females significantly produce estrogens.The three major naturally estrogens in women are estrona (E1), 17-β-estradiol (E2) e o estriol (E3). Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. Numerous reports in the literature postulates that estrogens play an important cardioprotective role, and that this protective action may occur either by expression of genes but also by activating signaling cascade of proteins that culminates in cardiovascular protection. However, in the brainstem the role of estrogen is still not fully understood. In the brainstem, specifically neuron located in the bulb region, plays an important role in the neuronal control of the cardiovascular system because they act both on the control of sympathetic activity as well as the reception of chemical and mechanical signals. In addition to this neuronal network of sympathetic control and decoding of afferent signals, the brain stem is under the influence of the actions of reactive oxygen species-EROS, these molecules having high ability to induce the oxidation of membrane lipids, proteins or even leading to nuclear DNA to a frame defined by oxidative stress which appears as a major cause of neurological diseases such as Parkinson's, Alzheimer, Amyotrophic lateral sclerosis among others. Thus the aim of the present reviewwasinvestigated the neuromodulator effects of the estrogens on female offsprings from dams that received low protein diet during.
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Thomas-Ahner, Jennifer M. "Gender differences in UVB induced cutaneous inflammation and skin carcinogenesis." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1179949864.

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Omoike, Ogbebor Enaholo. "Association of Perfluorinated Chemicals with Endocrino-Carcinogenetic, Obesogenic and Metabolic Health and with Markers of Chronic Inflammation and Oxidative Stress." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etd/3733.

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First, this study examined the association of perfluorinated chemicals with 1) cardio-metabolic health outcomes and 2) the association of phthalates with cardiometabolic health outcomes, and 3) cardio-metabolic health outcomes while assessing the possibility of additive interactions between perfluorinated chemicals (PFCs) and phthalates. Second, association with markers of chronic inflammation and oxidative stress were explored. Finally, this study examined the association of these chemicals with estrogenic cancers- Breast cancer, prostate cancer, uterine cancer and ovarian cancer. Using data from the National Health and Nutrition Examination Survey (NHANES), logistic regression models were used to investigate the relationship between PFCs and the cardio-metabolic health outcomes adjusting for covariates. An interaction term between PFCs and phthalates was added to the main effect model to assess the possibility of effect modification. Generalized linear models were used to examine associations between PFCs and inflammatory and oxidative stress markers per unit increase in exposure to PFCs while adjusting for covariates. Binomial logistic regression was used in investigating the association between quartiles of PFCs and presence or absence of cancer while also adjusting for covariates. Discriminant analysis was used to assess the correlation between individual PFCs compounds and individual cancer categories. Perfluorononanoic acid (PFNA) was associated with increased odds of central obesity in females, odds ratio (OR): 1.10; 95% confidence interval (CI): (1.01, 1.21). Perfluorohexane sulfonic acid (PFHS), Perfluorononanoic acid (PFNA), Perfluorooctanoic acid (PFOA), Perfluorooctane sulfonic acid (PFOS), and Perfluorodecanoic acid (PFDE) were all significantly associated with lymphocyte counts. Beta (95% CI); 0.03(0.02,0.05), 0.04(0.02,0.05), 0.05(0.03, 0.07), 0.04(0.03,0.05), 0.03(0.01,0.04) and with serum iron 0.07(0.05,0.09), 0.04(0.02,0.07), 0.10(0.07,0.12), 0.05(0.03,0.07), 0.04(0.02,0.06) and serum albumin 0.02(0.02,0.02), 0.02(0.02,0.03), 0.03(0.03,0.04), 0.02(0.02, 0.023), 0.01 (0.01, 0.05). Only PFHS, PFNA, PFOA and PFOS were associated with serum total bilirubin 0.04(0.03,0.05), 0.02(0.00,0.03), 0.06(0.04,0.08), 0.03(0.02,0.05). PFCs studied were associated with increased odds of breast, prostate, uterine and ovarian cancers, p
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Nedstrand, Elizabeth. "Applied relaxation as treatment of vasomotor symptoms in postmenopausal women /." Linköping : Linköpings universitet, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med900s.pdf.

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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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Alabed-Alibrahim, Eid. "Régulation de l’angiogenèse par le chlordécone : implication du stress oxydatif et de la mitochondrie." Thesis, Angers, 2016. http://www.theses.fr/2016ANGE0053.

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Des études épidémiologiques ont démontré que l’exposition aux pesticides tels que le chlordécone augmente le risque du cancer, en particulier de la prostate. Il avait été précédemment montré au laboratoire que le chlordécone possède des propriétés pro-angiogéniques impliquant la libération de NO et la production de VEGF suite à l’activation du récepteur aux oestrogènes de type alpha (ERα). Les processus angiogéniques pouvant impliquer les espèces réactives de l’oxygène (EROs), produites notamment par la mitochondrie, l’objectif de ce travail a été d’évaluer la contribution de la biogenèse mitochondriale et du stress oxydatif dans l’angiogenèse induite par le chlordécone.Les résultats obtenus montrent que la biogenèse mitochondriale n’est pas essentielle pour la réponse angiogénique du chlordécone puisqu’elle n’est retrouvée que pour de forte concentration de chlordécone. Les mécanismes mis en jeu ont été identifiés au niveau des cellules endothéliales humaines. Ils impliquent une régulation spatio temporellede la production des EROs impliquant dans un premier temps la NADPH oxydase, elle même capable de stimuler la production mitochondriale d’EROs via la voie impliquant la NO synthase. Le chlordécone serait par ailleurs capable de favoriser la localisation périnucléaire des EROs afin de favoriser la production de VEGF. L’ensemble de ces effets implique le récepteur aux oestrogènes. Ce travail a donc permis d’identifier les mécanismes cellulaires impliqués dans la modulation de l’angiogenèse par le chlordécone. Ces mécanismes moléculaires pourraient contribuer à identifier de nouvelles cibles permettant de réguler les processus angiogéniques et la tumorigenèse induites par ce toxique
Epidemiological studies report that exposure to pesticides like chlordecone increases risk of prostate cancer and tumorigenesis. We have reported recently that the pro-angiogenic effect of chlordecone involving NO release and VEGF production is mediated through activation of α isoform of the estrogen receptor (ERα). Since mitochondria and ROS have been implicated inthe process of angiogenesis, this study aims to determine the contribution of mitochondrial biogenesisand oxidative stress in chlordecone-induce dangiogenesis. Firstly, our results indicate that mitochondrial biogenesis is not essential for chlordecone angiogenic response. We also identified the molecular mechanism involved; chlordecone induces endothelial cells angiogenesis by a spatiotemporal regulation of ROS production involving NADPH oxidase then mitochondrial O2 -via a NO sensitive pathways through activation of ERα.These findings propose that a molecular mechanism may partly explain the epidemiological evidence implicating chlordecone as risk factor of prostatic cancer
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Costa, Tiago Januário da. "Testosterona abole os efeitos vasculoprotetores no tratamento com conjugado estrogênio equino (PREMARINâ) em ratas espontaneamente hipertensas ovariectomizadas." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-13112012-111255/.

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Os efeitos vasculares da associação de estrogênios e testosterona, utilizada para tratamento do distúrbio de desejo sexual hipoativo na pós-menopausa ainda não estão elucidados. O objetivo do trabalho foi avaliar as respostas vasculares ao tratamento de ratas espontaneamente hipertensas ovariectomizadas (SHR-OVX) com o conjugado estrogênio equino (CEE) associado ou não a cipionato de testosterona (CEE+T). O tratamento de SHR-OVX com CEE promove melhora da função endotelial na aorta por mecanismos que envolvem a redução da geração de espécies reativas de oxigênio (EROs) e aumento da expressão proteica de enzimas antioxidantes. O tratamento com CEE+T inibe os efeitos vasculoprotetores do CEE sobre o endotélio, aumentando a geração de EROs e diminuindo a expressão da enzima óxido nítrico sintase. A maior geração de EROs na aorta do grupo CEE+T parece depender da ativação de receptores AT1 de angiotensina II, da maior ação de fator inflamatório o 20-HETE e da ativação da enzima NADPH oxidase.
The vascular effects of estrogens and testosterone association, used for hypoactive sexual desire disorder treatment in postmenopausal women, have not been elucidated. The aim of this study was to evaluate the vascular effects of female ovariectomized (OVX) SHR treatment with conjugated equine estrogen (CEE) associated or not with testosterone cypionate (CEE+T). Our data shows that treatment of OVX-SHR with CEE improved endothelial function reducing reactive oxygen species (ROS) generation and increasing some antioxidant cellular mechanisms. Treatment with CEE+T blunted the vascular effects of CEE, increasing ROS generation and reducing eNOS expression. The increased ROS in CEE+T rats aorta seems to involve in angiotensin II-AT1 activation, 20-HETE action and NADPH oxidase activation.
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Coma, Camprodón Mireia. "Vascular aspects of Alzheimer's disease: role of oxidative stress on vascular miocytes B-amyloid production and B-amyloid-induced toxicity in endothelial cells." Doctoral thesis, Universitat Pompeu Fabra, 2007. http://hdl.handle.net/10803/7110.

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En aquest treball de tesis doctoral s'estudia el paper de l'estrès oxidatiu tant a la etiologia com a la patofisiologia del dany vascular associat a la malaltia d'Alzheimer. Es demostra la capacitat de les cèl·lules musculars llises vasculars de produir pèptid β-amiloide (Aβ). L'estrès oxidatiu associat a edats avançades, estimula el processament amiloidogènic de l' APP a cèl·lules musculars llises vasculars portant a un augment de producció d' Aβ1-40 i Aβ1-42 contribuint així, a la formació dels depòsits amiloides vasculars. Alhora, els depòsits amiloides vasculars indueixen dany vascular a través d'estrès oxidatiu, a on la nitrotirosinació de proteïnes juga un paper clau en la inactivació d'enzimes essencials per la viabilitat cel·lular. La vitamina E i els estrogens tenen un efecte protector a neurones i cèl·lules musculars llises vasculars mentre que la vitamina E, però no els estrogens, és capaç de protegir les cèl·lules endotelials davant la toxicitat induïda pel pèptid Aβ.
In this thesis we study the effect of oxidative stress in the etiology and pathophysiology of the vascular damage associated to Alzheimer's disease. We demonstrate the production of amyloid-β-peptide (Aβ) by vascular smooth muscle cells. Oxidative stress related to advance ages, induces the amyloidogenic APP cleavage producing an increase of Aβ1-40 and Aβ1-42 by vascular smooth muscle cells, which in tum contribute to vascular amyloid deposits generation. Vascular amyloid deposits induce oxidative stress, in which protein nitrotyrosination plays a key role in essential enzymes inactivation. Vitamin E and estrogens are able to protect neurons and vascular smooth muscle cells while vitamin E, but not estrogens, is able to protect endothelial cells against Aβ-mediated toxicity.
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Camporez, João Paulo Gabriel. "Efeitos do deidroepiandrosterona (DHEA) sobre a função vascular e a resistência periférica à insulina em um modelo experimental de menopausa." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-25072012-111253/.

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A administração de deidroepiandrosterona (DHEA) tem resultado em efeitos anti-diabetogênicos em animais de experimentação e no homem. Assim, o objetivo desse trabalho foi avaliar o efeito do DHEA sobre a função vascular em aorta e resistência periférica à insulina em roedores fêmeas ovariectomizadas (modelo experimental de menopausa - OVX). O tratamento com DHEA em ratas OVX, embora não levou a nenhuma alteração da composição corporal, induziu a uma redução na pressão arterial sistólica e disatólica, além de uma melhora na função vascular, aumentando a resposta à ACh e reduzindo a resposta à fenilefrina. Isso foi associado a uma redução do estresse oxidativo e inflação na aorta das ratos OVX. Para estudo da resistência à insulina foram utilizadas camundongos fêmeas OVX alimentadas com dieta hiperlipídica. O tratamento com DHEA nesses animais levou a uma redução do percentual de gordura corporal, provavelmente devido a uma redução da ingestão calórica. Também foi observado um aumento da sensibilidade à insulina nos animais tratados com DHEA, associado a uma redução do acúmulo ectópico de lipídios (fígado e músculo). Concluímos que o DHEA pode ser uma possível altenativa de tratamento, ao invés de estradiol, em mulheres na menopausa, já que ele é capaz de melhorar a função vascular e perfil metabólico em modelo experimental de menopausa.
Dehydroepiandrosterone (DHEA) treatment has resulted in anti-diabetogenic effects in both animals and humans. The aim of this study was to evaluate the effect of DHEA on vascular function in the aorta and peripheral insulin resistance in ovariectomized female rodents (experimental model of menopause - OVX). Although DHEA treatment in OVX rats did not lead to any change in body composition, it induced a decrease in blood pressure, and an improvement in vascular function, increasing the ACh response and reduces the response to phenylephrine. This was associated with a reduction in oxidative stress and inflammation in the aorta of OVX rats. For the study of insulin resistance it was used OVX female mice fed with high fat diet. DHEA treatment in these animals led to a reduction in body fat percentage, probably due to a reduction in caloric intake. It was also observed an increase in insulin sensitivity in animals treated with DHEA, associated with a reduction in ectopic fat (liver and muscle) accumulation. We conclude that DHEA may be a possible alternative treatment instead of estradiol, in postmenopausal women, since he is able to improve vascular function and metabolic profile in an experimental model of menopause.
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Martins, Danieli Brolo. "17-β Estradiol e resveratrol nos parâmetros bioquímicos e hematológicos de ratas ovariectomizadas submetidas a desmielinização pelo brometo de etídio." Universidade Federal de Santa Maria, 2012. http://repositorio.ufsm.br/handle/1/4067.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Among the neurodegenerative diseases those involving the demyelination of the nervous system, such as multiple sclerosis (MS) that affects young and middle-aged adults, have great importance. Thus, the goal of this study was to evaluate 17-β estradiol and resveratrol as promising substances due to their antioxidant and anti-inflammatory actions, in the neuronal and non-neuronal cholinergic system, hematologic and behavioral parameters in ovariectomized rats under or not the demyelination by ethidium bromide (EB). In the article, animals were randomly assigned into three experimental groups of each age. Control groups consisted of adult (sham-A) and middle-aged (sham-MA) female rats, ovariectomized adult (OVX-A) and middle-aged (OVX-MA) rats without estrogen therapy reposition, and ovariectomized adult (OVX+E2-A) and middle-aged (OVX+E2-MA) rats treated with 17-β estradiol for 30 days. After this period, AChE activity and lipid peroxidation were measured in the brain, blood and lymphocytes.The results showed that the acetylcholinesterase (AChE) activity increased in the striatum (ST) of adult ovariectomized animals with and without estrogen replacement and middle-aged animals without replacement, as well as in the hippocampus (HP) of middle-aged animals without hormone replacement. The inhibition of the AChE activity occurred in the ST of adult animals with estrogen replacement, in the cerebral cortex (CC) of adult animals with estrogen replacement, as well as in middle-aged animals with and without hormone replacement. The AChE activity of whole blood increased in adult animals with estrogen supplementation and decreased in middle-aged animals without 17-β estradiol. The AChE activity of lymphocytes was stimulated in adult animals with or without estrogen replacement, and it was inhibited in the middle-aged animals without estrogen replacement. There was an increase in lipid peroxidation in brain structures of all adult ovariectomized animals and cerebellum and cerebral cortex of middle-aged ovariectomized animals. In the manuscripts, the animals were divided into 5 groups to evaluate the demyelination phase and 5 groups to evaluate the remyelination phase. In each phase the groups were: control sham rats; ovariectomized rats, not demyelinated; demyelinated ovariectomized rats; ovariectomized rats, not demyelinated, treated with 17-β estradiol; and demyelinated ovariectomized rats treated with 17-β estradiol. In the manuscript 1, we investigate the effects of 17-β estradiol supplementation under the parameters related to the AChE activity in the brain, total blood and lymphocytes, as well as serum butyrylcholinesterase (BuChE) activity for a period of 7 or 21 days.Ovariectomy associated with EB increased the AChE activity in all structures in demyelination and remyelination phases. Estrogen supplementation stabilized the AChE activity in demyelination and inhibited the enzyme activity in the CC, ST and cerebellum (CE) in the remyelination, besides preventing cognitive impairment induced by ovariectomy. The BuChE activity showed elevation in demyelination and inhibition in remyelination in demyelinated animals treated with 17-β estradiol. The blood AChE activity showed an increase in demyelinated, non-demyelinated with estrogen replacement and demyelinated with estrogen replacement animals in both phases. In the demyelination phase, the AChE activity of lymphocytes showed an increase in the demyelinated group, while other groups have shown inhibition of this enzyme activity. In the manuscript 2, we evaluated the effect of resveratrol on The complete blood count and AChE activity of lymphocytes. The use of resveratrol for seven days decreased the AChE activity in ovariectomized animals and animals with ovariectomy and demyelination, without changing the number of circulating cells, demonstrating that there is no correlation between the circulating lymphocytes and the AChE activity of these cells. Taken together, these results show that 17-β estradiol and resveratrol modulate the AChE activity. The effects of estrogen therapy are dependent on the age and brain structure to be analyzed. Low levels of estrogen are detrimental to the cholinergic system. The damaging effects of ovariectomy can be potentiated in the presence of demyelination, which are generally reversed by the use of 17-β estradiol. This study therefore contributes to a better understanding for the use of estrogen replacement therapy and alternative therapies, such as resveratrol, in menopausal conditions and, especially, neurodegenerative diseases, such as MS, which pursue the process of demyelination. If these results are ratified in humans, these substances can be considered new therapeutic strategies for women.
Dentre as doenças neurodegenerativas, as que causam desmielinização do sistema nervoso central tem grande importância, como a esclerose múltipla (EM) que acomete adultos jovens e de meia-idade. Neste sentido, o 17-β estradiol e o resveratrol surgem como substâncias promissoras devido as suas ações antioxidante, antiinflamatória e neuroprotetora. Assim, o objetivo do presente estudo foi verificar o efeito do 17-β estradiol e do resveratrol nos parâmetros bioquímicos e hematológicos em ratas ovariectomizadas submetidas ao modelo de desmielinização pelo brometo de etídio (BE). No primeiro artigo, os animais foram separados em 3 grupos experimentais para cada idade. Os grupos consistiram de controles adultos (Sham-A) e de meia-idade, ratas ovariectomizadas adultas e de meia-idade e ratas ovariectomizadas com reposição por 30 dias com 17-β estradiol adultas e de meia-idade. Após este período, a atividade da AChE foi mensurada no encéfalo,sangue total e linfócitos, e a peroxidação lipídica foi mensurado apenas no encéfalo. Os resultados obtidos demonstraram que a atividade da acetilcolinesterase (AChE) aumentou no estriado (ST) de ratas adultas ovariectomizadas sem e com reposição estrogênica, e de meia-idade sem reposição. No hipocampo (HP) também foi observado um aumento na atividade desta enzima apenas nas ratas de meia idade sem reposição do hormônio. A inibição na atividade da AChE ocorreu no ST e no córtex cerebral (CC) de ratas adultas com reposição estrogênica e nas ratas de meia-idade com e sem reposição hormonal. A atividade da AChE aumentou no sangue total de ratas adultas com reposição estrogênica e diminuiu nas ratas de meia-idade sem 17-β estradiol. Nos linfócitos foi observado um aumento na atividade da AChE de ratas adultas com ou sem reposição de estrógeno, e inibida no grupo de meia-idade sem reposição estrogênica.Houve um aumento na peroxidação lipídica em todas as estrituras encefálicas dos animais adultos ovariectomizados e córtex cerebral e cerebelo dos animais de meia-idade ovariectomizados.. Nos manuscritos, os animais foram divididos em 5 grupos para avaliar a fase de desmielinização e outros 5 grupos para avaliar a fase de remielinização. Em cada fase, os grupos consistiram de ratas controle; ratas ovariectomizadas; ratas ovariectomizadas e desmielinizadas; ratas ovariectomizadas tratadas com 17-β estradiol (maunscrito 1) ou resveratrol (manuscrito 2); e ratas ovariectomizadas e desmielinizadas tratadas com 17-β estradiol (manuscrito 1) ou resveratrol (manuscrito 2). No manuscrito 1, investigou-se os efeitos do 17-β estradiol sobre os parâmetros relacionados a atividade da AChE encefálica, do sangue total e dos linfócitos, e atividade da butirilcolinesterase (BuChE) por um período de 7 ou 21 dias. Quando a ovariectomia foi associada a desmielinização pelo BE foi observado um aumento na atividade da AChE em todas as estruturas estudadas, na desmielinização e na remielinização A suplementação estrogênica estabilizou a atividade da AChE na desmielinização e inibiu a atividade da enzima no CC, ST e cerebelo (CE) na remielinização, além de conseguir prevenir o prejuízo cognitivo induzido pela ovariectomia. A atividade da butirilcolinesterase (BuChE) aumentou na fase de desmielinização e esteve inibida na fase de remielinização nas ratas tratadas com 17-β estradiol. Já a AChE sanguínea apresentou elevação de sua atividade nas ratas desmielinizadas, não-desmielinizadas com reposição estrogênica e desmielinizadas com reposição estrogênica em ambas as fases. A atividade da AChE dos linfócitos aumentou nas ratas desmielinizadas, enquanto nos demais grupos houve uma inibição na atividade desta enzima na fase de desmielinização. No manuscrito 2, avaliou-se o efeito do resveratrol no hemograma e na atividade da AChE de linfócitos. Apenas o uso do resveratrol por 7 dias diminuiu a atividade da AChE nos linfócitos de ratas submetidas a ovariectomia e nas ratas com ovariectomia e desmielinização, sem alterar o número dos linfócitos na circulação. Assim, os resultados obtidos neste estudo demonstraram que o 17-β estradiol e o resveratrol modulam a atividade da AChE neuronal e não-neuronal. Os efeitos da terapia estrogênica são dependentes da idade e da estrutura encefálica a ser analisada. Além disso, a queda estrogênica é prejudicial ao sistema colinérgico. Os efeitos danosos da ovariectomia podem ser potencializados na presença de desmielinização, sendo estes em grande parte revertidos com o uso do 17-β estradiol. Assim, este estudo colabora para uma melhor compreensão do uso da terapia de reposição estrogênica e terapias alternativas, como o resveratrol, em condições menopáusicas e, principalmente, em doenças neurodegenerativas que cursem com o processo de desmielinização, como a EM. Se ratificados estes resultados na espécie humana, estes compostos poderão ser considerados novas estratégias terapêuticas para as mulheres.
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21

Nascimento, Ezequiel Batista do. "Efeitos de diferentes tipos estressores sobre a mem?ria e aprendizagem de ratas." Universidade Federal do Rio Grande do Norte, 2013. http://repositorio.ufrn.br:8080/jspui/handle/123456789/17355.

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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
The exposure to stressors produces physiological changes of the organism in order to adapt the individual to the environment. Depending on the type, intensity and duration, stress can affect some cognitive functions, particularly processes of learning and memory. Several studies have also proposed that some level of anxiety would be necessary for memory formation. In this context, memories of previously aversive experiences may determine the manner and intensity with which are expressed fear responses, which explains the great interest in analyzing both anxiety and memory in animals. In addition, males and females demonstrate different reactions in relation to stressful stimuli, showing different levels of anxiety and differences in processing of the acquisition, retention and recall of information. Based on this information, the present study aimed to verify the effect of stress on learning, memory and anxiety behavioral parameters in rats exposed at different types of stressors of long duration (seven consecutive days): restraint (4h/day), overcrowding (18h/day) and social isolation (18h/day) in the different phases of the estrous cycle. Our results showed that the stress induced by restraint and social isolation did not cause changes in the acquisition process, but impaired the recall of memory in rats. Furthermore, it is suggested a protective effect of sex hormones on retrieval of aversive memory, since female rats in proestrus or estrus phase, characterized by high estrogen concentrations, showed no aversive memory deficits. Furthermore, despite the increased plasma levels of corticosterone observed in female rats subjected to restraint stress and social isolation, anxiety levels were unaltered, compared to those various stress conditions. Animal models based on psychological and social stress have been extensively discussed in the literature. Correlate behavioral responses, physiological and psychological have contributed in increasing the understanding of stress-induced psychophysiological disorders
A exposi??o a fatores estressantes promove mudan?as fisiol?gicas adaptativas do organismo ao meio ambiente. Dependendo do tipo, da intensidade e dura??o, o estresse pode afetar algumas fun??es cognitivas, particularmente o processo de aprendizagem e de mem?ria. Alguns estudos tamb?m t?m proposto que a ansiedade, em certa medida, seria necess?ria para que ocorresse a forma??o da mem?ria. Neste contexto, mem?rias de experi?ncias aversivas anteriores podem determinar a maneira e a intensidade com que s?o expressas as respostas de medo, o que justifica o grande interesse em analisar simultaneamente ansiedade e mem?ria em animais. No mais, machos e f?meas apresentam rea??es distintas em rela??o a est?mulos estressores, mostrando diferentes n?veis de ansiedade e diferen?as no processamento da aquisi??o, reten??o e evoca??o de informa??es mnem?nicas. Frente a essas informa??es, o presente estudo teve como objetivo verificar o efeito do estresse em par?metros comportamentais de aprendizagem, mem?ria e ansiedade de ratas submetidas a diferentes tipos de estressores de longa dura??o, (sete dias consecutivos): conten??o (4h/dia), alta densidade populacional (18h/dia) e isolamento social (18h/dia), nas diferentes fases do ciclo estral. Nossos resultados mostraram que o estresse promovido pela conten??o e pelo isolamento social n?o promoveram altera??es no processo de aquisi??o, mas promoveu preju?zos na evoca??o da mem?ria de ratas. Al?m disso, sugere-se um efeito protetor dos horm?nios sexuais sobre a evoca??o da mem?ria aversiva, uma vez que ratas que estavam nas fases proestro ou estro, fase de altas concentra??es plasm?ticas de estr?genos, n?o apresentaram preju?zos na evoca??o dessa mem?ria. No mais, apesar do aumento dos n?veis plasm?ticos de corticosterona observado nas ratas submetidas ao estresse de conten??o e isolamento social, os n?veis de ansiedade permaneceram inalterados frente a essas diferentes condi??es de estresse. Modelos animais baseados em estresse psicol?gico e social t?m sido bastante abordados na literatura. Correlacionar respostas comportamentais, fisiol?gicas e psicol?gicas t?m contribu?do no aumento da compreens?o dos transtornos psicofisiol?gicos envolvidos na resposta de estresse
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22

Hajjar, Julia. "The Effects of Gestational and Lactational Bisphenol A Exposure on Rat Pup Morphometric Measurements and on Adrenal Gland Glucocorticoid Receptor Gene Expression." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36163.

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Endocrine Disrupting Chemicals (EDC) are exogenous agents that mimic endogenous hormone activity in the body. EDC exposure during the critical period of neonatal development can potentially cause life-long neurological, behavioural and physiological disease. This thesis focuses on the EDC Bisphenol A (BPA), a synthetic xenoestrogen widely prevalent in everyday materials that has significant environmental relevance given its ubiquitous presence in humans around the world. The central research question of my thesis is: Does perinatal exposure to BPA affect rat pup development? A rodent model was selected to study the effects of BPA on the adrenal component of the hypothalamic-pituitary-adrenal axis (HPA axis) stress pathway, which has not been extensively studied. Rat dams were divided into five groups (vehicle control (VEH), positive control diethylstilbestrol (DES), BPA 5, BPA 50 and BPA 500 μg/kg bw/day) and dosed daily throughout gestation and for four days of lactation. Rat pups were sacrificed at two time-points at the beginning and the end of the stress hyporesponsive period (SHRP), at postnatal day (PND) 5 and PND 15. Changes in three morphometric parameters (bodyweight, crown-rump (CR) length and anogenital distance (AGD) were assessed based on the factors of Treatment and Sex. Adrenal gland glucocorticoid receptor (GR) and 18SrRNA expression was determined by qPCR in male pups at PND 5 and PND 15. At PND 5, compared to the VEH group, the BPA 50 pups were significantly heavier (ANOVA, Dunnett’s post-hoc) and the DES and BPA 50 pups had significantly longer CR lengths (ANOVA, Dunnetts’ post-hoc). At PND 15, xenoestrogen treatment significantly influenced CR length (ANOVA). At both time-points, males had significantly longer AGD than females, as physiologically expected (ANOVA). Adrenal gland GR expression in male pups was not significantly affected by treatment, but there was an effect of treatment in18SrRNA gene expression at PND 5 (Kruskal-Wallis). Using the Ct method to determine GR and 18SrRNA fold changes, we cautiously suggest that our experimental doses resulted in a non-monotonic dose response to BPA in the PND 5 animals and a monotonic dose response to BPA exposure in the PND 15 animals. This study highly values the importance of investigating the effects of environmentally relevant, low dose BPA exposure during the critical window of development, given the little that is known about potentially permanent alterations to the stress pathway due to exposure during this delicate period of development.
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23

Araujo, Priscila Xavier de. "Efeitos do conjugado estrogênio eqüino (Premarin&#210) sobre o leito venular mesentérico de SHR ovariectomizadas: papel do endotélio." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-24052012-091149/.

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Ainda existe controvérsia se a terapia hormonal estrogênica confere benefício ou dano cardiovascular. O dano potencial causado por doses padrão de estrogênio incluindo doença cardíaca coronariana e trombose venosa pode ser atenuada por uso de doses mais baixas. O objetivo deste estudo foi avaliar o efeito do tratamento com conjugado estrogênio equino, no leito mesentérico venular (LVM) de SHR ovariectomizadas (OVX), com dose padrão (SD) vs dose mínima (LD). Angiotensina II (AngII) foi perfundida de forma concentração-dependente. Hiperreatividade à Ang II, aumento na geração de EROS, redução da atividade da SOD e catalase e da biodisponibilidade do NO foram encontrados em OVX e SD vs controle e LD. Por outro lado, a resposta reduzida à AngII no LVM de ratas LD foi relacionado ao aumento da atividade da eNOS, redução na geração de EROS e aumento da expressão dos receptores AT2,ERα e GPR30. Sugerimos que a dose mínima tem efeito protetor sobre o LVM das OVX e que a dose SD pode aumentar o risco para a doença venular induzindo alterações na reatividade venular.
Controversy still exists whether estrogen hormonal therapy confers cardiovascular benefit or harm. The potential harm caused by standard dosages of estrogen including coronary heart disease and venous thrombosis may be mitigated by use of lower doses. The aim of this study was evaluated the effect of conjugated equine estrogen (CEE) treatment, in isolated mesenteric venular bed (MVB) of ovariectomized SHR (OVX), at standard therapeutic (SD) vs low dose (LD). Angiotensin II (Ang II) was perfused in a concentration-dependent manner. Hyperreactivity to Ang II,augmented ROS generation, reduced SOD, catalase activity and NO availability were found in OVX and SD vs. control and LD. However, the reduced MVB response to Ang II in LD rats was related to increased endothelial NO synthase activity, reduced ROS generation and increased Ang II AT2, ERα and GPR30 receptor expression. We suggest that CEE at a low dose has a protective effect in OVX mesenteric venular bed. The standard dose might increase the risk for venular disease by inducing alterations in venular reactivity.
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24

Victorino, Vanessa Jacob. "Mecanismos de proliferação celular dependentes da atividade do coativador - 1 de receptor ativado por proliferadores de peroxissoma gama (PGC-1)." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5167/tde-22012016-113027/.

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Apesar dos avanços no tratamento dos diferentes subtipos moleculares do câncer de mama, diversos efeitos colaterais e resistência ao tratamento são observados. Nesse contexto, a busca por novos marcadores moleculares ainda é necessária. A família do coativador - 1 do receptor ativado por proliferadores de peroxissoma gama-1 (PGC-1) exerce funções cruciais no metabolismo energético celular e alguns trabalhos na literatura mostram alterações de PGC-1 no desenvolvimento do câncer. Contudo, mecanismos envolvidos na proliferação celular do carcinoma de mama permanecem desconhecidos. O objetivo geral foi determinar os mecanismos pelos quais PGC-1 controla a proliferação de células tumorais de mama, com foco em vias metabólicas e de sinalização redox. Para alcançar os objetivos, foi determinada a expressão de PGC-1alfa e beta em células tumorais de mama dos subtipos moleculares luminal (MCF-7), HER2- superexpresso (SKBR3) e triplo negativo (MDAMB231) em relação a uma linhagem de mama não tumoral (MCF-10A). Foi encontrada maior expressão gênica e proteica de PGC-1beta na superexpressão de HER2, e maior taxa de crescimento para essa linhagem. Para investigar se PGC-1beta pode estar envolvido na proliferação dessas células, utilizamos sequências específicas de RNA de interferência para o knockdown de PGC-1beta nas células SKBR3. Após o tratamento houve diminuição de proliferação celular. Assim, investigamos os prováveis mecanismos pelos quais PGC-1beta diminui a proliferação celular. Nossos resultados mostram que o knockdown de PGC-1beta não influenciou a expressão de ciclinas (B, C, D e E) e não houve diferença na quantidade de DNA mitocondrial, fator de transcrição mitocondrial A (TFAM), fator de respiração nuclear (NRF) 1 e 2. Em seguida, mostramos que o knockdown de PGC-1beta diminuiu a produção de lactato intracelular e aumentou a atividade da enzima citrato sintase, e houve tendência a maior taxa de respiração celular. Detectamos maiores níveis de espécies reativas de oxigênio (EROs) após knockdown de PGC-1beta enquanto que a produção de nitrito e nitrato, não diferiu. Não houve alteração na atividade das enzimas antioxidantes superóxido dismutase, catalase e sistema glutationa. Os resultados revelam presença de despolarização mitocondrial quando PGC-1? é diminuído nas células HER2. Como os receptores relacionados a estrógeno (ERR) possuem conhecido papel na regulação do metabolismo energético, avaliamos se sua expressão é modulada por PGC-1?. A diminuição de PGC-1beta não influenciou a expressão gênica de ERRy e reduziu a expressão gênica de ERRalfa. Por fim, mostramos maior expressão de PGC-1beta proveniente de tumores de pacientes com câncer de mama HER2- superexpresso em relação aos diferentes subtipos moleculares. Conclui-se que a diminuição da sinalização por HER2/ PGC-1beta/ ERRalfa está envolvida com a diminuição da via glicolítica e aumento da via oxidativa com consequente aumento de EROs e perda do potencial de membrana mitocondrial, resultando em diminuição da proliferação celular. Espera-se que os resultados desse estudo ajudem na identificação de vias de sinalização importantes que controlam tanto o metabolismo energético quanto a proliferação de células tumorais, as quais poderão se tornar alvos terapêuticos no futuro
Despite a marked improvement in treatments for all breast cancer subtypes, several side-effects and resistance to therapy are noticed. In this context, the searching for new molecular targets for breast cancer treatment is still a challenge. Peroxisome proliferator-activated receptor- gamma coactivator 1 (PGC-1) is the main regulator of cell energy homeostasis and studies in the literature show alterations regarding PGC-1 in cancer development. However, mechanisms involved in cellular proliferation of breast cancer remain unknown. We aimed to determine the mechanisms by which PGC-1beta controls breast cancer cell proliferation, focusing on metabolic and redox signaling. To reach this goal, we determined PGC-1alfa and beta expression in breast cancer cell lines as luminal (MCF-7), HER2-overexpressed (SKBR3) and triple- negative (MDAMB231) as compared to a non-tumoral breast cell line (MCF-10A). We found increased gene and protein expression of PGC-1beta in HER2- overexpressed cells and increased cellular proliferation. To investigate whether PGC-1beta could be involved in the proliferation of those cells, we used specific sequences of silencing interfering RNA for knockdown of PGC-1beta in SKBR3 cells. After treatment we observed a decrease in cellular proliferation. Thus, we next investigated the probable mechanisms by which PGC-1beta could decrease cellular proliferation. Our results showed that knockdown of PGC-1beta did not influence on cyclin expression (B, C, D and E), mitochondrial DNA number, mitochondrial transcription factor - A (TFAM), nuclear receptor factor (NRF) 1 and 2 expression. We showed that knockdown of PGC-1beta induced a decrease intracellular lactate production, increase in citrate synthase activity and a trend to increase cellular respiration rate. Thereby, we detected greater amounts of reactive oxygen species (ROS) after knockdown of PGC-1beta, and no alterations was found for nitrite and nitrate levels. No alterations regarding antioxidant enzymes activities as superoxide dismutase, catalase, and glutathione system were found. Results revealed loss of mitochondrial membrane potential when PGC-1beta is decreased in HER2- overexpressed cells. As estrogen related receptors (ERR) have a recognized role in the regulation of energetic metabolism, we assessed whether their expression could be modulated by PGC-1beta. The decrease in PGC-1beta expression did not influence on ERRy expression, but it decreased the gene expression of ERRalfa. Finally, we demonstrated increased PGC-1beta expression in HER2- overexpressing tumors from breast cancer patients. Taken together, we conclude that decrease in HER2/ PGC-1beta/ ERRalfa signaling may be related to decrease in glycolytic pathway and increase in oxidative metabolism resulting in increased ROS production and loss of mitochondrial membrane potential, which can lead to decreased cellular proliferation. We hope that the findings may help in the identification of important cellular signaling that may control energetic metabolism regarding tumor cells proliferation, which can became future target therapies
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25

Miragem, Antônio Azambuja. "Efeito agudo do tratamento térmico nos níveis de HSP70 e marcadores de estresse oxidativo de ratas wistar." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/127427.

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Os fogachos são a queixa mais comum das mulheres peri- e pós-menopausa e estão fortemente relacionados com a diminuição dos níveis de estrogênio. No entanto, a fisiopatologia deste sintoma vasomotor muito desagradável é ainda desconhecido. Por outro lado, o estradiol (E2) apresenta a capacidade de induzir a expressão de HSP72, um membro da família de 70 kDa das proteínas de choque térmico (HSP70), que são citoprotetoras e cardioprotetoras. Sabe-se que a expressão HSP70 é comprometida em doenças inflamatórias relacionadas com o envelhecimento. Por isso, questionamos se a capacidade do organismo de desencadear uma resposta ao choque térmico (Heat Shock Response) robusta, estaria ainda presente após a retirada, via castração, do E2. Para tanto, foram estudados os efeitos do choque térmico (Heat Shock - HS), através de uma sessão de banho de imersão, em ratas Wistar submetidas a ovariectomia bilateral (OVX), após um período de washout hormonal de 7 dias. Doze horas após o HS, os animais foram mortos e o arco aórtico foi excisado cirurgicamente para análises moleculares. Os resultados foram comparados com os marcadores de estresse oxidativo no plasma (superóxido dismutase, catalase e lipoperoxidação), pois é bem estabelecido que a expressão de HSP70 é sensível a regulação redox. A relação entre a iHSP70 (intracelular) e a eHSP70 (extracelular/plasma), proposto como um índice do estado inflamatório sistêmico, também foi investigada. Os resultados mostraram que a Heat Shock Response continua preservada em animais OVX, como inferido a partir da expressão de HSP70 (até 40% de aumento, p <0,01) nas aortas, o que não foi acompanhado por nenhuma outra alteração em marcadores de estresse oxidativo, parâmetros hematológicos e no controle glicêmico. Desta forma, sugerimos que a avaliação periódica do status de HSP70 (iHSP70 vs eHSP70) pode ser de extrema relevância clínica, pois a diminuição da capacidade de defesa do organismo via Heat Shock Response está no centro do aparecimento de disfunções relacionadas com a menopausa.
Hot flashes, the most common complaint of peri- and postmenopausal women, are tightly related to decrease in estrogen levels. However, the pathophysiology of this very unpleasant vasomotor symptom is greatly unknown. On the other hand, estradiol (E2) has been found to induce the expression of HSP72, a member of the 70 kDa family of heat shock proteins (HSP70), which are cytoprotective and cardioprotective. Since it has been noticed that HSP70 expression is compromised in age-related inflammatory diseases, we argued whether the capacity of triggering a robust heat shock (HS) response would be still present after E2 withdrawal. Hence, we studied the effects of HS treatment (hot tub) in female Wistar rats subjected to bilateral oophorectomy (OVX) after a 7 day washout period. Twelve hours after HS, the animals were killed and aortic arches were surgically excised for molecular analyses. The results were compared with oxidative stress markers in the plasma (superoxide dismutase, catalase and lipoperoxidation) because HSP70 expression is sensitive to redox regulation. Extracellular (plasma) to intracellular HSP70 ratio, an index of systemic inflammatory status, was also investigated. The results showed that HS response was preserved in OVX animals, as inferred from HSP70 expression (up to 40% rise, p<0.01) in the aortas, which was accompanied by no further alterations in oxidative stress, hematological parameters and glycemic control either. As a consequence, periodic evaluation of HSP70 status (iHSP70 vs eHSP70) may be of clinical relevance because decreased HS response capacity is at the center of the onset of menopause-related dysfunctions.
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26

Brooks, Bryan W. "Ecotoxicological Investigations in Effluent-Dominated Stream Mesocosms." Thesis, University of North Texas, 2002. https://digital.library.unt.edu/ark:/67531/metadc3359/.

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The University of North Texas Stream Research Facility (UNTSRF) was designed to examine contaminant impacts on effluent-dominated stream ecosystems. Stream mesocosms, fed municipal effluent from the City of Denton, TX, Pecan Creek Water Reclamation Plant (PCWRP), were treated with 0, 15 or 140 µg/L cadmium for a 10-day study in August 2000. Laboratory toxicity test and stream macroinvertebrate responses indicated that cadmium bioavailability was reduced by constituents of effluent-dominated streams. The Biotic Ligand Model (BLM) for Cd was used to predict a 48 hour Cd EC50 for Ceriodaphnia dubia of 280 µg/L in these effluent-dominated streams. This value is higher that an EC50 of 38.3 µg/L Cd and a 7-day reproduction effect level of 3.3 µg/L Cd generated for C. dubia in reconstituted laboratory hard water. These results support use of a cadmium BLM for establishing site-specific acute water quality criteria in effluent-dominated streams. Although not affected by 15 µg/L treatments, organisms accumulated Cd in 15 µg/L treated streams. Hence, over longer exposure periods, Cd accumulation may increase and a no effect level may be lower than the observed 10-day no effect level of 15 µg/L. A toxicity identification evaluation procedure was utilized with in vitro and in vivo bioassays to identify estrogenic compounds in PCWRP effluent, previously identified to seasonally induce vitellogenin (VTG) in male fathead minnows. Steroids, nonylphenol ethoxylate metabolites, and other unidentified compounds were identified as causative effluent estrogens. These findings suggest that in vivo VTG bioassays should be used to confirm in vitro Yeast Estrogen Screening assay activity when effluents are fractionated or screened for estrogenicity. A subsequent 90-day cadmium study was initiated to assess long-term effluent and cadmium effects on fish endocrine function. Juvenile fathead minnows were placed in UNTSRF pool sections of replicate streams treated with 0, 5, 20 or 80 µg/L Cd. Male VTG was induced at each treatment level, indicating that PCWRP effluent was estrogenic during fall 2001. 20 and 80 µg/L Cd treatments reduced male circulating estradiol levels and critical swimming performance. Future studies are needed to assess impacts of environmental estrogen exposure on fish calcium metabolism and vertebral integrity.
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27

Adania, Cristina Harumi. "Estudo endócrino não invasivo e comportamental da gestação, parto e lactação da jaguatirica (Leopardus pardalis) em cativeiro." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/10/10131/tde-02032010-141827/.

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Os perfis longitudinais dos metabólitos dos esteróides sexuais, progesterona e estrógenos, e dos glicocorticóides foram analisados para 22 eventos (gestação, parto e lactação) de 8 jaguatiricas mantidas em cativeiro. Três eventos foram oriundos da Transferência de Embrião (TE) e foram comparados àquelas que gestaram por fertilização natural. As análises estatísticas demonstraram haver diferenças altamente significativas para metabólitos de progesterona na fase inicial (P<0001) e média (P< 0,007) da gestação, bem como, no período da lactação (P<0,0015). As análises descritivas sugeriram uma atividade ovariana para a espécie no período de lactação, uma vez detectado picos de metabólitos de estrógenos para alguns eventos. Foi realizado ainda, um estudo do comportamento materno de 3 fêmeas através do sistema de vídeo-monitoramento dos primeiros meses da lactação (n=3989,5 horas observadas). A espécie em cativeiro despendeu mais tempo cuidando do seu filhote e descansando durante o dia, entrando na caixa de abrigo entre 5:00h e 8:00h (61,3%) e nela permanecendo por um tempo médio de 8 horas seguidas. Outras análises comportamentais sugerem que o estresse é um fator preponderante na determinação do sucesso da criação do filhote. A variável comportamental executada pela fêmea de entrar e sair da caixa por repetidas vezes foi associada ao estresse, sendo possível avaliar a resposta da adrenal pela secreção dos glicocorticóides e realizar sua validação fisiologicamente. Espera-se desta forma, contribuir para uma mudança no quadro bastante crítico da população em cativeiro, considerando a baixa taxa de natalidade e a alta taxa de mortalidade dos filhotes, principalmente, no seu primeiro mês de vida.
The longitudinal profiles of the sexual steroid\'s metabolites, progesterone and estrogen, and glucocorticoids were analyzed for 22 events (pregnancy, birth and breastfeeding) of 8 ocelots kept in captivity. Three events came from the Embryo Transfer (TE) and were compared against the ones that were gestated by natural fertilization. The statistical analysis demonstrated that the differences were highly significative during the initial (P<0001) and middle stages (P< 0,007) of pregnancy and lactation (P<0,0015) periods for the progesterone metabolites. The descriptive analysis suggests a ovarian activity for the species during the lactation period, once detected the estrogen metabolites peaks during some events. A study was also performed, concerning the maternal behavior of 3 female through video-monitoring of the first months of lactation (n=3989,5 hours observed). The species that were kept in captivity spent more time resting and caring the puppy, entering it\'s shelter between 5:00h and 8:00h (61,3%) and there staying during 8 hours average. Other behavior analysis suggests that the stress level is a predominant fact in the success of the establishment of the puppy. A behavior variable performed by the female, by entering the shelter for a repeated number of times was linked to the stress level, being possible to assess the adrenal response by the secretion of glucorticoids and perform it\'s phisiological validation. It is expected by this means, a contribution for a change in the critical scene of the population that is kept in captivity, considering the puppies\' low birth rate and high mortality rate, specially during it\'s first months.
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28

Bonacasa, Fernández Bárbara. "Efecto del 2-metoxiestradiol en el remodelado vascular inducido por la hipertensión." Doctoral thesis, Universidad de Murcia, 2007. http://hdl.handle.net/10803/10866.

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OBJETIVO: Estudiar el efecto del tratamiento con 2-metoxiestradiol en el remodelado vascular miocárdico inducido por la hipertensión y tras una lesión vascular por denudación endotelial en arteria femoral.MATERIAL Y MÉTODOS: modelo de hipertensión: se han utilizado 5 grupos experimentales de ratas SHR de 10 semanas de vida: rata hembra intacta, rata hembra ovarioectomizada, rata hembra ovarioectomizada y tratada con 2-metoxiestradiol, rata macho y rata macho tratada con 2-metoxiestradiol. Se les midió la presión por pletismografía una vez por semana hasta la semana 18. En la semana 18 se les extrae en corazón y los vasos del lecho mesentérico para realizar los protocolos de análisis de la estructura vascular miocárdica y de producción de anión superóxido y expresión de proteínas relacionadas con la proliferación celular. Modelo de lesión vascular: se han utilizado 5 grupos experimentales de ratas SD: rata hembra intacta, rata hembra ovarioectomizada, rata hembra ovar ioectomizada y tratada con 2-metoxiestradiol, rata macho y rata macho tratada con 2-metoxiestradiol. A la semana de establecer los grupos, se les realiza la cirugía de lesión endotelial por denudación y a las dos semanas se extrae la muestra y se cuantifica la formación de neoíntima.RESULTADOS: Modelo de Hipertensión: Existen diferencias entre sexos en las ratas SHR, tanto en la evolución de la Hipertensión como en el remodelado vascular miocárdico, en la actividad de la NADPH oxidasa vascular de lecho mesentérico y en los factores protéicos de proliferación celular. El tratamiento con 2-metoxiestradiol atenuó el aumento de la presión arterial sistólica provocada por la ovarioectomía así como en el remodelado vascular miocárdico. En la expresión de proteínas y en la actividad de la enzima NADPH oxidasa disminuyó pero no de forma significativa. En las ratas macho, el tratamiento con 2-metoxiestradiol atenuó la evolución de la hipertensión, el remodelado vascular miocárdico, e l incremento de la actividad de la enzima NADPH oxidasa y los factores de proliferación celular. Modelo de Lesión Vascular: No hemos observado diferencias entre sexos en la formación de neoíntima. La ovarioectomía provocó un incremento en la formación de neoíntima y el tratamiento con 2-metoxiestradiol atenuó dicho incremento. En ratas macho, este metabolito no mostró efecto ninguno.
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29

Harms, Christoph Friedemann. "Endogene Systeme der Neuroprotektion." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2003. http://dx.doi.org/10.18452/14874.

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Die Wirkung von zwei endogen neuroprotektiven Substanzen, Melatonin und 17 beta-Estradiol wurde an drei Caspase-abhängigen, apoptotischen, aber Exzitotoxin-unabhängigen Schadensmodellen an neuronalen Primärkulturen untersucht und mit der bei vorwiegend nekrotischen Schadensmodellen verglichen. Es zeigten sich eine Abhängigkeit des neuroprotektiven Potentials von der Art des Zelluntergangs sowie unterschiedliche Mechanismen der Neuroprotektion. Melatonin wirkte in allen drei apoptischen Modellen nicht neuroprotektiv, sondern verstärkte die Schädigung der Neurone noch, während partiell gegen die OGD-induzierte Nekrose (OGD, engl. Oxygen glucose deprivation, kombinierter Sauerstoff- und Glukoseentzug) kortikaler Neurone Schutz erzielt wurde. Der Einsatz des endogenen neuroprotektiven Faktors Melatonin als Therapeutikum ist möglicherweise nur bei neurodegenerativen Erkrankungen mit exzitotoxischer Schädigung durch Glutamat oder oxidativem Stress wie bei Epilepsie oder dem Schlaganfall durch Ischämie sinnvoll. Die fehlende bzw. potenzierenden Wirkung von Melatonin bei neuronaler Apoptose in vitro, stellt jedoch einen therapeutischen Erfolg bei der Behandlung der mit apoptotischer Schädigung einhergehenden Alzheimer'schen Erkrankung in Frage. Bei klinischer Anwendung ist auch der von uns erhobene Befund zu beachten, dass in vitro native neuronale Zellen durch Melatonin geschädigt werden. 17 beta-Estradiol wirkte sowohl bei nekrotischer als auch bei apoptotischer Zellschädigung. Dabei zeigten sich wesentliche Unterschiede in den Mechanismen der Neuroprotektion und in der Ansprechbarkeit verschiedener Regionen des Gehirns. Schutz vor Apoptose konnte nur durch eine Langzeitvorbehandlung (20 h) in septalen und hippokampalen Kulturen, nicht jedoch in kortikalen Kulturen beobachtet werden. Dieser Effekt liess sich durch Rezeptorantagonisten, Proteinsynthesehemmung sowie durch Hemmung der Phosphoinositol-3-Kinase blockieren. Eine Kurzzeitbehandlung war gegen Apoptose nicht wirksam, zeigte gegen OGD und Glutamattoxizität jedoch neuroprotektives Potential. Dieser Effekt liess sich nicht antagonisieren, so dass hier ein direkter antioxidativer Mechanismus wahrscheinlich erscheint. Die antiapoptotische Wirkung in septalen und hippokampalen Kulturen korrelierte mit einer höheren Dichte des Estrogenrezeptors-alpha und einer erhöhten Expression antiapoptotischer Proteine in diesen Regionen. Da bei der Alzheimer'schen Erkrankung der Kortex betroffen ist, könnte der fehlende Effekt von 17 beta-Estradiol in kortikalen Neuronen sowohl auf die neuronale Apoptose als auch auf die Proteinexpression von Bcl-2 und Bcl-xL möglicherweise auf experimenteller Basis erklären, warum eine langfristige Estrogentherapie bei Frauen mit milder bis moderater Alzeimer'scher Erkrankung den Progress der Erkrankung nicht aufhalten konnte (Mulnard et al. 2000).
The neuroprotective effect of melatonin and 17 beta-estradiol has been evaluated in several in vitro models of neuronal apoptosis and necrosis. Melatonin was not neuroprotective in three models of apoptosis but showed a pro-apoptotic effect in primary cortical neurons. Melatonin revealed to damage naïve neurons, too. Partial protection was observed against necrotic neurodegeneration after oxygen-glucose deprivation (OGD). The use of melatonin as a therapeutic agent might be of interest in neurodegenerative diseases with excitotoxic damage like epilepsia or ischemia, but is questioned in case of apoptotic neurodegeneration. 17 beta-estradiol was neuroprotectiv in both necrotic and apoptotic neurodegeneration. Differences in the mechanism of neuroprotetion and in the efficacy in different regions of the brain were observed. A neuroprotective effect was visible only in hippocampal and septal cultures if 17 beta-estradiol was applied 20 h prior (long term pre-treatment) but not in cortical neurons. This effect correlates with an increased density of estrogen receptor-alpha and an increased expression of anti-apoptotic proteins like Bcl-2 and Bcl-xL in these regions. These effect could be blocked with receptor antagonists, protein synthesis inhibitors and an inhibitor of the phosphatidylinositol 3-kinase. A short term pre-treatment revealed a receptor independent neuroprotective potential against OGD and glutamate toxicity. The failure of 17 beta-estradiol to protect cortical neurons against apoptosis could be an experimental basis to understand, why a long lasting treatment with estrogens of women with mild to moderate Alzheimer´s disease failed to inhibit the progress of the illness (Mulnard et al., 2000)
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30

Nadal, Casellas Antònia. "Diferències de sexe en els efectes de l'obesitat sobre el procés de biogènesi mitocondrial. Relació amb la sensibilitat a la insulina." Doctoral thesis, Universitat de les Illes Balears, 2010. http://hdl.handle.net/10803/362907.

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Introducció Existeixen diferències de gènere en la capacitat oxidativa mitocondrial del teixit adipós marró (TAM) i del fetge de rata, que s’atribueixen a la presència de mitocondris més diferenciats i funcionals a les femelles que als mascles. Una situació d’excés de nutrients, com és el cas de l’obesitat dietètica, podria desencadenar un estat d’estrès oxidatiu i alterar el funcionament mitocondrial com a conseqüència de canvis en el procés de biogènesi mitocondrial. Encara que els mecanismes pels quals l’obesitat dietètica modifica el funcionament mitocondrial no estan completament establerts, s’ha suggerit una connexió entre la via de senyalització de la insulina i el procés de biogènesi mitocondrial. Contingut de la investigació L’eix central d’aquesta tesi ha estat l’estudi de la influència del gènere en els efectes que té l’obesitat sobre la funció i biogènesi mitocondrials del TAM i del fetge, i establir la relació amb la sensibilitat tissular a la insulina. Per assolir aquest objectiu, en primer lloc, s’han analitzat els efectes que té l’alimentació crònica amb una dieta hiperlipídica sobre els paràmetres de funció i biogènesi mitocondrials, l’estat redox i els elements claus en la via de senyalització de la insulina al TAM i al fetge de rates d’ambdós gèneres. En segon lloc, s’ha usat un model de rates femella ovariectomitzades per aprofundir en el coneixement de la influència de les hormones ovàriques sobre el procés de biogènesi mitocondrial. Els resultats obtinguts han demostrat que les diferències de gènere en el funcionament mitocondrial poden atribuir-se, en part, a les hormones ovàriques i que els efectes de l’obesitat sobre el funcionament mitocondrial i la sensibilitat a la insulina són dependents del gènere. En comparació amb els mascles, l’alimentació amb la dieta hiperlipídica indueix a les rates femella un major guany de pes corporal, una major acumulació de greix al teixit adipós blanc i un augment de la resistència a la insulina, tant a nivell circulant com en el TAM i del fetge. Per una banda, la pèrdua de sensibilitat a la insulina del TAM de les rates femella pot estar relacionada amb la disminució de la capacitat oxidativa mitocondrial del teixit i amb l’augment del dany oxidatiu. Per altra banda, la incrementada resistència a la insulina en el fetge de les rates femella, i el manteniment d’una major capacitat oxidativa mitocondrial, en comparació als mascles, es poden considerar mecanismes de protecció enfront de la lipotoxicitat hepàtica induïda per la dieta. Conclusió En el seu conjunt, els resultats obtinguts en aquesta tesi demostren que els efectes de l’obesitat sobre el funcionament mitocondrial també depenen del teixit. Mentre que al fetge de les rates d’ambdós gèneres es posen en marxa mecanismes per fer front a l’excés de nutrients que permeten assolir una nova situació d’equilibri i evitar el dany oxidatiu, al TAM només s’observa una resposta compensatòria en els mascles, el que estaria relacionat amb les diferències de gènere observades en el guany de pes corporal.
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31

Nadal, Serrano Mercedes. "Efectos de los Estrógenos, la Genisteína y la Leptina sobre el Estrés Oxidativo en el Cáncer de Mama. Importancia de la UCP2." Doctoral thesis, Universitat de les Illes Balears, 2014. http://hdl.handle.net/10803/284237.

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El estrés oxidativo es un desequilibrio entre la producción de radicales libres y los sistemas antioxidantes encargados de su neutralización. El resultado de este desequilibrio es la acumulación de daños en diversas estructuras celulares incluyendo el DNA. El cáncer se acompaña de un mayor estrés oxidativo a nivel celular, por este motivo, muchos de los tratamientos terapéuticos van dirigidos a aumentar los niveles citotóxicos de ROS, conduciendo a la célula tumoral a la apoptosis. Sin embargo, durante la tumorigénesis las células van adquiriendo una serie de características que permiten mantener la homeostasis de los ROS y desarrollar resistencia a los tratamientos antineoplásicos. El cáncer de mama es un tipo de neoplasia en la que el factor endocrino juega un papel relevante tanto en la etiología como en la evolución de la enfermedad. En esta tesis nos planteamos como objetivo estudiar los efectos del 17β-estradiol (E2), la genisteína y la leptina, como factores hormonales, sobre la modulación del estrés oxidativo en la carcinogénesis de mama. E2 es uno de los principales factores de riesgo en la iniciación y progresión de la enfermedad; la genisteína es uno de los fitoestrógenos de mayor actividad estrogénica y, por su parte, la leptina también ha mostrado efectos potenciadores sobre el cáncer de mama, considerándose a nivel epidemiológico como un posible enlace entre obesidad y cáncer. Para alcanzar estos objetivos se estudió: i) el efecto dual de E2 y genisteína sobre el estrés oxidativo en función de la dotación de ERα y ERβ en líneas celulares de cáncer de mama (MCF-7 y T47D), y el estrés oxidativo en muestras de carcinomas ductales infiltrantes en función de la ratio de receptores estrogénicos; ii) la influencia de la leptina crónica sobre el estrés oxidativo y su respuesta al fármaco antineoplásico cisplatino en la línea celular MCF-7; y iii) la importancia de la UCP2 en la regulación del estrés oxidativo endógeno e inducido en las células MCF-7, así como, en líneas celulares de cáncer de páncreas con p53 mutado. Los resultados indican que E2 induce estrés oxidativo de forma dependiente de la dotación de ERα/ERβ. Así, el aumento del estrés oxidativo, debido en parte a un descenso de los sistemas antioxidantes, está mediado por ERα. En cambio, la activación de ERβ por la genisteína implica un menor estrés oxidativo y una mejor función mitocondrial, promovido por una respuesta antioxidante. En consonancia con el estudio in vitro, los carcinomas mamarios con una menor ratio ERα/ERβ también mostraron una mayor respuesta detoxificante, favoreciendo la supervivencia celular. Por su parte, la leptina parece disminuir el nivel de estrés oxidativo basal, lo que podría jugar un papel en la adquisición de resistencia a los tratamientos anticancerígenos. El desacoplamiento mitocondrial mediado por UCP2 protege a la célula cancerosa del daño oxidativo, lo que posiblemente podría conferir citoprotección a través de la adquisición de quimioresistencia. En células de cáncer de páncreas, p53 mutado induce la producción de ROS debido a una disminución de UCP2, contribuyendo al crecimiento celular. En conclusión, los resultados de la presente tesis sugieren que tanto ERβ como UCP2 podrían ser biomarcadores interesantes para conseguir una mejor caracterización del tumor en relación a su nivel de estrés oxidativo y la posible respuesta al tratamiento.
L'estrès oxidatiu és un desequilibri entre la producció de radicals lliures i els sistemes antioxidants encarregats de la seva neutralització. El resultat d'aquest desequilibri és l'acumulació de danys a diverses estructures cel•lulars incloent el DNA. El càncer va acompanyat d'un major estrès oxidatiu a nivell cel•lular, per aquest motiu, molts dels tractaments terapèutics van dirigits a augmentar els nivells citotòxics de ROS, conduint a la cèl•lula tumoral a la apoptosi. No obstant això, durant la tumorigènesi les cèl•lules van adquirint una sèrie de característiques que permeten mantenir l'homeòstasi dels ROS i desenvolupar resistència als tractaments antineoplàstics. El càncer de mama és un tipus de neoplàsia en la qual el factor endocrí juga un paper rellevant tant en la etiologia como en l'evolució de la malaltia. En aquesta tesi ens vàrem plantejar com a objectius estudiar els efectes del 17β-estradiol (E2), la genisteïna i la leptina, com a factors hormonals, sobre la modulació de l'estrès oxidatiu en la carcinogènesi de mama. E2 és un dels principals factors de risc en la iniciació i progressió de la malaltia, la genisteïna és un dels fitoestrògens de major activitat estrogènica i, per la seva part, la leptina també ha mostrat efectes potenciadors sobre el càncer de mama, considerant-se a nivell epidemiològic un possible enllaç entre obesitat i càncer. Per a assolir aquests objectius es va estudiar: i) l'efecte dual de E2 i genisteïna sobre l'estrès oxidatiu en funció de la dotació de ERα i ERβ en línies cel•lulars de càncer de mama (MCF-7 i T47D), i l'estrès oxidatiu a mostres de carcinomes ductals infiltrants en funció de la ràtio de receptors estrogènics; ii) la influència de la leptina crònica sobre l'estrès oxidatiu i la seva resposta al fàrmac antineoplàstic cisplatí en la línea cel•lular MCF-7; i iii) la importància de la UCP2 en la regulació de l'estrès oxidatiu endogen i induït en les cèl•lules MCF-7, així como, en línies cel•lulars de càncer de pàncrees amb p53 mutat. Els resultats indiquen que E2 indueix estrès oxidatiu de forma depenent de la dotació de ERα/ERβ. Així, l'augment de l'estrès oxidatiu, causat en part per un descens dels sistemes antioxidants, està mediat per ERα. En canvi, l'activació de ERβ per la genisteïna implica un menor estrès oxidatiu i una millor funció mitocondrial, promogut per una resposta antioxidant. En consonància amb l'estudi in vitro, els carcinomes mamaris amb una menor ràtio ERα/ERβ també varen mostrar una major resposta detoxificant, afavorint la supervivència cel•lular. Per la seva part, la leptina sembla disminuir el nivell d'estrès oxidatiu basal, la qual cosa podria jugar un paper en l'adquisició de resistència als tractaments anticancerígens. El desacoblament mitocondrial mediat per UCP2 protegeix a la cèl•lula cancerosa del dany oxidatiu, fet que possiblement podria conferir citoprotecció a través de l'adquisició de quimioresistència. En cèl•lules de càncer de pàncrees, p53 mutat indueix la producció de ROS a causa d'una disminució de UCP2, contribuint al creixement cel•lular. En conclusió, els resultats de la present tesi suggereixen que tant ERβ com UCP2 podrien ser biomarcadors interessants per a aconseguir una millor caracterització del tumor en relació al seu nivell d'estrès oxidatiu i la possible resposta al tractament.
Oxidative stress is an imbalance between free radical production and the antioxidant systems responsible for counteracting them. The result of this imbalance is accumulation of damage in several cellular structures, including DNA. Cancer is associated with increased oxidative stress, therefore, many therapeutic treatments are targeted to raise cytotoxic ROS levels, which would lead to tumor cell apoptosis. However, during tumorigenesis, cells acquire several features that maintain ROS homeostasis and develop resistance to anticancer treatments. Breast cancer is a type of neoplasia in which the endocrine factor plays an important role in etiology and disease progress. In the preset thesis we set out to study the effects of hormonal factors: 17β-estradiol (E2), genistein and leptin, on oxidative stress modulation in breast carcinogenesis. E2 is one of the main risk factors for breast cancer initiation and progression; genistein is one of the phytoestrogens with greater estrogenic activity and, while, leptin has also shown enhancing effects on breast cancer, epidemiologically it is also considered to be a possible link between obesity and cancer. The aim of this work was to study: i) the dual effect of E2 and genistein on oxidative stress depending on the ERα and ERβ ratio in breast cancer cell lines (MCF-7 and T47D), and oxidative stress in invasive ductal carcinoma samples depending on estrogen receptor ratio; ii) the influence of chronic leptin on oxidative stress and response to anticancer drug cisplatin in MCF-7 cell line; iii) the significance of UCP2 in the regulation of endogenous and induced oxidative stress in MCF-7 cells as well as in mutant p53 pancreatic cancer cell lines. Results indicate that E2 induces oxidative stress in a ERα/ERβ ratio-dependent manner. Thus, the increase in oxidative stress, due to in part to a decrease in antioxidant systems, is mediated by ERα. In contrast, ERβ activation by genistein involves a lower oxidative stress and better mitochondrial function, which is promoted by an antioxidant response. In agreement with the in vitro study, breast tumors with a lower ERα/ERβ ratio showed a higher detoxifying response, which also improved cellular survival. In turn, leptin appears to decrease the basal level of oxidative stress, which could play a role in the acquisition of resistance to anticancer treatments. UCP2-mediated mitochondrial uncoupling protects the cancer cell from oxidative damage, which may possibly confer cytoprotection through chemoresistance acquisition. In pancreatic cancer cells, p53 mutant induces ROS production due to a decrease in UCP2, contributing to cell growth. In conclusion, the results of this thesis suggest that both ERβ and UCP2 may be interesting biomarkers for a better characterization of the tumor in relation to its level of oxidative stress and possible treatment response.
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32

Stubbins, Renee Elaine. "Estrogen modulates adiposity and protects against obesity-associated inflammation, oxidative stress, and insulin resistance." Thesis, 2012. http://hdl.handle.net/2152/ETD-UT-2012-05-5013.

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Obesity is associated with numerous co-morbidities, such as chronic low-grade inflammation, oxidative stress, insulin resistance, cardiovascular disease, and some cancers. However, the role of estrogen in the susceptibility to obesity and its co-morbidities is not clear. To determine the role of estrogen in the above morbidities, we used C57BL/6J mice (15/group): 1)males 2)nonovariectomized females (novx) 3)ovariectomized females (ovx) and 4) ovariectomized females supplemented with estrogen (ovx-E), which were randomized to receive a 30% calorie-restricted, low-fat or high-fat diet. Our results showed that male and ovx-female mice were more susceptible to obesity compared to novx-female and ovx-female+E mice. Specifically, we observed that estrogen protected novx-female and ovx-female+E mice from adiposity and glucose intolerance by decreasing adipocyte size and key adipogenic and lipogenic mRNA expression levels. Further experimentation established that estrogen decreased abdominal adiposity by decreasing the number of large adipocytes. Our findings implied that estrogen stimulated lipolysis in novx-female and ovx-female+E mice. Additionally, the enlarged adipocytes observed in the male and ovx-female mice were accompanied with crown-like structures surrounding necrotic adipocytes and F480+ macrophages and elevated mRNA expression levels of CD68, IL6, and TNF[alpha]. Lastly, male and ovx-female mice exhibited liver steatosis, elevated serum ALT levels, and increased insulin resistance. To determine if there were sex differences in oxidative stress, we showed that estrogen protected the novx-female and ovx-female+E mice from adipose tissue oxidative stress as evidenced by fewer γH2AX stained nuclei and lower iNOS, P47x, GP90x, but higher catalase mRNA levels. In order to further understand the role of estrogen in adipocyte inflammation, we differentiated 3t3L1 pre-adipocytes in charcoal-stripped FBS +/- 1nM estrogen. Our findings mimicked our in vivo results; the presence of estrogen significantly decreased adipogenesis and down regulated IL6, TNF[alpha], and GP90x in 3t3L1 adipocytes. Additionally, using 4-hydroxytamoxifen, we demonstrated that the protective effects of estrogen on IL6 and TNF[alpha] mRNA expression were blocked; suggesting that estrogen could mediate its anti-inflammatory effects through ERα. In conclusion, this dissertation demonstrates that estrogen protects female mice from obesity-associated inflammation, oxidative stress, and insulin resistance by altering adipocyte morphology possibly through ER[alpha].
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33

Chang, Yao-ju, and 張曜如. "Estrogen modulates sexually dimorphic contextual fear conditioning and stress-induced impairment of LTP." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/25709954090663325186.

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碩士
國立成功大學
藥理學研究所
96
Females and males are different in brain and behavior. Differences begin early during development due to a combination of genetic and hormonal events and continue throughout the lifespan of an individual. Females are more susceptible than males to stress-induced affective disorders and twice as likely to experience depression. These differences are probably underlined by sexual dimorphisms observed in the hypothalamic-pituitary-adrenal (HPA) axis activity/response to stress and its interaction with the central neurotransmitter systems. In this study, we investigated whether sex alters behavioral and physiological responses to stress and estrogen exerts both organizational and activational influence on the sex differences in response to stress. Using pharmacological, biochemical and behavioral techniques, we have found that levels of hippocampal CA1 long-term potentiation (LTP) induction vary across the estrous cycle and estrogen contributes greater amount of LTP in proestrus and estrus females. A significant positive linear correlation is evident between the plasma estradiol levels and the magnitude of LTP expression in females. Male rats exhibited significantly higher levels of contextual fear freezing and stress-induced impairment of LTP than female rats. The sexually dimorphic extinction of contextual fear conditioning is mediated, at least in part, through an estrogen-dependent mechanism. An estrogen receptor (ER) �� agonist diarylpropionitrile (DPN) but not an ER �� agonist propyl-pyrazole-triol (PPT) also facilitataes the extinction of contextual fear memory in ovariectomized female rats, suggesting that estrogen-mediated facilitation of fear extinction involves the activation of ER��. Intrahippocampal injection of estradiol one hour before extinction training in ovariectomized female rats remarkably reduced the duration of freezing responses during the extinction training and test, compared with the vehicle-injected control rats. In addition, the locomotion or the anxiety state of female rats does not vary across the estrous cycle. We found no significant difference in acquisition and extinction of contextual fear memory between male and female at juvenile and adolescent ages. Taken together, these experiments reveal an important role for estrogen in modulating both sexually dimorphic contextual fear conditioning and hippocampal synaptic plasticity in response to stress. Understanding why individuals exhibit differential responses to stress-induced affective disorders is important to further the basic science of stress vulnerability as well as to effectively treat and perhaps prevent stress-related affective disorders in at-risk individuals.
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Hsu, Chin-Fu, and 許晉輔. "Effect of Estrogen on Mechanical Stress-induced Inflammatory Response in Ligamentum Flavum cell." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/55425059146638218943.

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碩士
國立陽明大學
醫學工程研究所
101
Ligamentum flavum hypertrophy leads to the formation of spinal canal with subsequent neural compression. Previous findings suggest that mechanical stresses induce inflammatory reactions and scar formation play an important role in the progression of ligamentum flavum hypertrophy. The normal ligamentum flavum is composed of 70% elastin protein and 30% collagen protein, but the composition ratio of elastin protein and collgen protein change in the elderly. Previous studies indicated the presence of estrogen receptors in tendons and ligament. Therefore, estrogen play an important role in the regulation of lastin protein and collgen protein. Inflammation has been proposed to be an important causative factor in ligamentum flavum hypertrophy. Mechanical force induces human ligamentum flavum fibroblasts inflammation. It also demonstrated estrogen and mechanical force are positive regulators for osteoblasts proliferation and bone formation. In addition, the expression of estrogen receptor was enhanced in calcium crystal deposit ligamentum flavum. In this study, we used human ligamentum flavum fibroblasts were obtained from twenty-one patients undergoing lumbar spine surgery. Centrifugal force induces inflammation of human ligamentum flavum fibroblasts, and then enter 10-9 M of estrogen. Hence, the aim of the present study was to investigate the effects of estrogen on mechanical stress-induced inflammatory response in ligamentum flavum cells. The investigation demonstrated that cell viability of ligamentum flavum fibroblast was no significant differences but rise trend and the cell viability was better in 10-9 M 17β-estradiol stimulation. Besides, The cell viability were the same reduction trend on mechanical or 17β-estradiol combined with mechanical stress stimulation groups when ligamentum flavum fibroblast treated centrifugal stimulation but had 17β-estradiol stimulation were better than mechanical stress stimulation. The IL-1α, IL-6 and TNF-α mRNA pro-inflammatory cytokines mRNA expression were indeed reduction by mechanical force stimulation but pretreated 17β-estradiol stimulation were inhibited expression. Finally, the intracellular MAPK signaling transduction pathways results were shown pro-inflammatory cytokines regulate through the p-ERK. This initial study suggested that estrogen inhibite on mechanical stress-induced inflammatory response in ligamentum flavum cell.
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35

Mühlfelder, Melanie. "Protektive kardiovaskuläre Effekte weiblicher Sexualsteroide - Estrogenrezeptoren reduzieren den Aldosteron-induzierten oxidativen Stress in glatten Gefäßmuskelzellen." Doctoral thesis, 2011. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-64943.

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Reaktive Sauerstoffspezies (ROS, engl. reactive oxygen species) sind hochreaktive Biomoleküle, die in geringen Konzentrationen ubiquitär als Produkte des normalen zellulären Metabolismus entstehen. Zum Schutz vor irreversiblen oxidativen Schädigungen durch diese Moleküle, besitzt der Organismus antioxidative Enzyme und nicht-enzymatische Antioxidantien, die ROS neutralisieren. Eine pathophysiologische Zunahme der Generierung und Freisetzung von ROS und/oder verminderte zelluläre Abwehrmechanismen gegen diese können, in Folge einer gestörten Redox-Homöostase, zur Ausbildung des sog. „oxidativen Stresses“ führen, der unter anderem mit einer Reihe kardiovaskulärer Erkrankungen assoziiert ist. Das Steroidhormon Aldosteron (ALDO), das der Gruppe der Mineralocorticoide angehört, besitzt für den Wasser- und Elektrolythaushalt eine essentielle Bedeutung. Als Agonist bindet ALDO an Mineralocorticoidrezeptoren (MR) in der Niere und im Kolon und stimuliert unter physiologischen Bedingungen über die Aktivierung des MR die renale Rückresorption von Natriumionen und Wasser. Epidemiologische Studien sowie in vitro und in vivo Untersuchungen konnten einen kausalen Zusammenhang zwischen erhöhten ALDO-Serumwerten und/oder einer disproportional erhöhten MR-Aktivierung und einer gesteigerten ROS-Generierung im Herz-Kreislaufsystem belegen. Im Gegensatz zu ALDO besitzt das Sexualsteroid 17β-Estradiol (E2) protektive kardiovaskuläre Effekte. E2 fungiert über zwei intrazelluläre Estrogenrezeptor (ER)-Subtypen, ERα und ERβ, die nach ligandabhängiger Aktivierung als nukleäre Transkriptionsfaktoren die Expression spezifischer Zielgene regulieren. Neben ER-vermittelten vasodilatatorischen und antiinflammatorischen Wirkungen innerhalb der Blutgefäße und des Myokards besitzt E2 unter anderem auch antioxidative Eigenschaften und das Potential die zelluläre Redox-Homöostase günstig zu beeinflussen. Auf Grund dieser Befunde wurde die Hypothese aufgestellt, dass E2 über einen ER-vermittelten Mechanismus dem ALDO-induzierten oxidativen Stress in glatten Gefäßmuskelzellen der Ratte (PRSMC, für engl. primary rat smooth muscle cells) entgegenwirkt. Zusätzlich sollte durch die Supplementation des ERα-spezifischen Agonisten 16α-LE2 und des ERβ-spezifischen Agonisten 8β-VE2 zu ALDO-behandelten Zellen untersucht werden, ob die beiden ER-Subtypen redundante, spezifische oder gegensätzliche Effekte bezüglich der aufgestellten Hypothese, besitzen. Durch Färbungen hormonbehandelter PRSMC mit dem ROS-sensitiven Fluoreszenzfarbstoff Dihydroethidium (DHE) und anschließender Quantifizierung der DHE-Fluoreszenzintensität konnte bestätigt werden, dass der ALDO-induzierte oxidative Stress durch die Kosupplementation von E2, 16α-LE2 und 8β-VE2 über einen ERα- und ERβ-vermittelten Mechanismus signifikant reduziert werden kann. Des Weiteren konnte im Verlauf dieser Arbeit belegt werden, dass die intrazelluläre Konzentration des Reduktionsäquivalents Nicotinamid-Adenin-Dinukleotid-Phosphat in seiner reduzierten Form (NADPH) in ALDO+E2-, ALDO+16α-LE2- und ALDO+8β-VE2-behandelten PRSMC im Vergleich zu nur mit ALDO-behandelten Zellen signifikant erhöht ist. Ferner konnte in Übereinstimmung mit diesen Ergebnissen gezeigt werden, dass die Kosupplementation von NADPH zu ALDO-behandelten Zellen, die DHE Oxidation in diesen Zellen signifikant unterbindet. Mittels Western Blot Analysen und Enzymaktivitätsassays hormonbehandelter PRSMC ließ sich schließlich nachweisen, dass ALDO die Enzymaktivität und Proteinexpression des NADPH generierenden Enzyms Glukose-6-phosphat Dehydrogenase (G6PDH) supprimiert. Weiter konnte innerhalb dieser Arbeit erstmalig bestätigt werden, dass E2 die Suppression der G6PDH-Aktivität durch ALDO unterbindet und die Enzymaktivität dieses Proteins wieder auf den basalen Wert anhebt. Zusammenfassend konnte in dieser Arbeit gezeigt werden, dass E2 der ALDO-induzierten lokalen ROS-Generierung in PRSMC ER-vermittelt entgegenwirkt. Der zugrunde liegende Mechanismus dieses Effekts basiert auf einer Aufrechterhaltung der G6PDH-Enzymaktivität, wodurch die Bioverfügbarkeit des Reduktionsäquivalents NADPH, das eine Schlüsselrolle im zellulären antioxidativen System spielt, gewährleistet wird
Reactive oxygen species (ROS) are highly reactive bio-molecules produced as by-products during normal cellular metabolism. Cells are protected against ROS by cellular antioxidative defense mechanisms like antioxidative enzymes and reducing equivalents. However, if the cellular redox state is disrupted and the balance between ROS generation and ROS elimination is excessive, ROS are able to cause oxidative stress which plays an important pathophysiological role in the development of cardiovascular diseases. The mineralocorticoid hormone aldosterone (ALDO) mediates electrolyte and volume balance via binding and activation of its mineralocorticoid receptor (MR) to elevate systemic blood pressure through renal effects. However, excessive or disproportional MR activation is associated with oxidative stress. This results in a decreased bio-availability of nitric oxide (NO) and inflammation in the vasculature leading to fibrosis, vascular remodelling and endothelial dysfunction thereby contributing to hypertension as well as renal and cardiac failure. In contrast to ALDO, the sex hormone 17β-estradiol (E2) is known to have beneficial cardiovascular effects. E2 acts via its cognate intracellular estrogen receptor (ER) subtypes ERα and ERβ which are defined as nuclear ligand-activated transcription factors. E2 procure cardio- and vasoprotective effects among others by its antioxidative properties. Based upon these findings we proposed the hypothesis that ALDO and E2 may have opposing effects on ROS generation in rat vascular smooth muscle cells (PRSMC). Furthermore, the co treatment of E2 and the specific ER-agonists 16α-LE2 and 8β-VE2 to ALDO-treated cells should reveal whether the two ER-subtypes mediate redundant, specific or opposing effects. Respective experiments of dihydroethidium (DHE) fluorescent microphotography and quantification of its fluorescence intensity revealed that ALDO-induced oxidative stress can be attenuated by E2, 16α-LE2 and 8β-VE2. This effect was mediated by ERα and ERβ. Further experiments demonstrated that intracellular levels of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) were significantly increased in ALDO-treated PRSMC co-supplemented with E2, 16α-LE2 and 8β-VE2. In good agreement with these findings, DHE fluorescence showed decreased ROS generation in ALDO treated cells after co-incubation with NADPH. Additionally, molecular and biochemical analyses gave evidence for restored activity and protein expression of the major intracellular NADPH generating enzyme glucose 6 phosphate dehydrogenase (G6PDH) in ALDO+E2 co-treated PRSMC; ALDO treatment alone caused a decrease in G6PDH activity and protein expression. Consequently, E2 can compensate the deleterious effects of ALDO in PRSMC via preservation of G6PDH activity. This enzyme stabilises bio-availability of NADPH, which in turn acts as a key player in cellular antioxidative defense
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36

Hayashi, Masaya. "Effects of pregnancy, estrogen, and shear stress on heat shock proteins in teh ovine uterine artery." 2004. http://catalog.hathitrust.org/api/volumes/oclc/56616157.html.

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Thesis (M.S.)--University of Wisconsin--Madison, 2004.
Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 133-151).
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37

Wu, Wing Man. "An investigation into the neuroprotective effects of estrogen and progesterone in a model of homocysteine-induced neurodegeration /." 2005. http://eprints.ru.ac.za/415/.

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38

Domazetovic, Vladana. "Protective role of antioxidants in bone and bowel pathological alterations related to oxidative stress." Doctoral thesis, 2018. http://hdl.handle.net/2158/1121581.

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Free radicals are common outcome of normal aerobic cellular metabolism and endogenous antioxidant system plays its decisive role in prevention of excessive amount of free radicals. However, imbalanced defence mechanism of antioxidants, overproduction or incorporation of free radicals from environment to living system leads to various pathological states. In particular, given the involvement of oxidative stress and antioxidants in bone remodelling alterations and inflammatory bowel diseases, the aim of this thesis was to study: 1) the role and molecular mechanisms of the physiologically predominant estrogen, 17β-Estradiol (17β-E2), and natural antioxidants on stress induced apoptosis in osteocytes; 2) the antioxidant ability of resveratrol (RE) and of its benzoselenophene derivatives, VD0, VD1 and VD2, in restoring the physiological redox state in both osteocytes and intestinal myofibroblasts; 3) the role of oxidative stress and TNFα on the expression and activation of TNF-α converting enzyme (TACE) involved in chronic intestinal inflammation. Estrogen deficiency causes bone loss as a result of microdamage, oxidative stress and osteocyte apoptosis. A relationship between oxidative stress-induced apoptosis, c-Jun N-terminal kinase (JNK) activation, and expression of factors involved in bone remodelling has been demonstrated in osteocytes. However, the molecular regulation of these events in osteocytes treated with 17β-E2 remains unexplored. The MLO-Y4 murine osteocyte-like cell line was used as a model to study starvation-induced apoptosis and ROS production during 17β-E2 treatment. Expression of glutathione S-transferase P1-1 (GSTP1-1), receptor activator kB ligand (RANKL), osteoprotegerin (OPG), sclerostin, and kinases activation were measured by western blot. In addition, the GSTP1-1/JNK association was assessed by immunoprecipitation, and GSTP1-1 involvement in the osteocyte response to 17β-E2 was detected by specific siRNA transfection. 17β-E2 prevents starvation-induced apoptosis (DNA fragmentation and caspase-3 activation), the increase in sclerostin expression and the RANKL/OPG ratio, which are all related to osteoclastogenic and JNK activation due to oxidative stress in osteocytes. Estrogen prevention occurs through GSTP1-1 overexpression, which can inhibit JNK activation by formation of a GSTP1-1/JNK complex. No early antioxidant effect of 17β-E2 has been found, however, the estrogen effect results similar to N-acetylcysteine which, by decreasing the intracellular oxidative state, maintains JNK bound to GSTP1-1. Thus, the antiapoptotic and osteogenic effect of 17β-E2 in MLO-Y4 occurs by a redox- independent process involving GSTP1-1/JNK association. Moreover, the role of blueberry juice (BJ) obtained from Vaccinium myrtillus berries, native in Italian Apennines, on ROS production, apoptosis and expression of osteoclastogenic factors in MLO-Y4 osteocytes, was investigated and compared to that of dry extracts of blueberry (BE), green tea (GTE) and Hypericum perforatum (HE), being the last two known for their powerful antioxidant properties and beneficial effects in reducing the bone mass loss. The results show that both fresh juice, and blueberry dry extract reduce the apoptosis and the expression of osteoclastogenic factors induced by oxidative stress in starved MLO-Y4 osteocytes in the same manner as GTE and HE containing equal amount of total soluble polyphenols. However, blueberry antiapoptotic effect is not closely related to its antioxidant effect in MLO-Y4 cells, differently to that observed in GTE- and HE-treated MLO-Y4 cells. This suggests that the effect of blueberries on osteocyte apoptosis and bone turnover can be due to their antioxidant properties but also to other factors, not strictly redox regulated, which remain to be elucidated in further studies. RE, a polyphenolic compound present in some food and plants, is characterized by anti-inflammatory and antioxidant properties. However, it is quickly metabolized with consequent loss of its efficacy. The antioxidant effect of 2-phenyl-benzoselenophene derivatives of RE (VD0, VD1 and VD2) was detected in human colon mucosa myofibroblasts, CCD-18Co (18Co), and in MLO-Y4 cells in which the oxidative stress was induced by buthionine sulfoximine (BSO), inhibitor of GSH synthesis, or serum starvation, respectively. The results show that RE derivatives have major antioxidant power in reducing and/or restoring radical oxygen species to control values respect to RE in both cell types. Moreover, derivatives have different antioxidant capacity in 18Co and in MLO-Y4 and this can be due to different degree of oxidative stress and structural characteristics of these compounds. Some of the synthesized RE analogues have shown antibacterial role in IBD and anti-resorptive activity in bone pathologies related to inflammatory and osteoporotic processes. Thus, it has been speculated the use of benzoselenophene derivatives as an alternative therapy and/or therapeutic support in intestinal inflammatory disease and osteoporosis. Finally, the role of oxidative stress and TNFα on the expression and activation of TACE has been investigated in 18Co cells treated with BSO and/or stimulated with TNFα. Previously, in these cells it has been shown that oxidative stress and TNFα are both related to an increased expression of ICAM-1 and release of sICAM-1 by a TACE proteolytic cleavage. In literature no data are reported on the expression, activation and regulation of this enzyme in relationship to the intracellular oxidative state in intestinal myofibroblasts. The data obtained indicate a strong relationship between TACE expression and activation and intracellular ROS levels. In fact, GSH depletion by BSO and TNFα, both increase ROS levels and TACE expression and activation, whereas N-acetylcysteine (NAC), precursor of GSH synthesis, and diphenyleneiodonium (DPI), inhibitor of NADPH oxidase, restore these events to control values, by reducing ROS levels. Given that TACE is involved in the cleavage of adhesion molecules and pro-inflammatory cytokines, which increase in condition of oxidative stress, antioxidants may have beneficial role in reducing the activation of inflammatory cascade and preventing the progression of chronic inflammatory disease.
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39

Bernardino, Ana Carolina de Matos. "Evaluation of the antioxidant action of the G protein-coupled estrogen receptor." Master's thesis, 2020. http://hdl.handle.net/10400.6/10803.

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The brain is characterized by a high metabolism and contains several easily oxidizable substances such as amines and lipids, resulting in exposure to high levels of oxidative stress. In Parkinson's disease (PD), oxidative stress has been shown to be correlated with lipid peroxidation, inflammation, mitochondrial dysfunction and aggregation of a-synuclein (asyn). This demonstrates that oxidative stress can be one of the triggers of Parkinson's disease, as it is capable of inducing a series of pathogenic mechanisms characteristic of the disease, contributing to its progression. In this sense, the identification of mechanisms that help reducing oxidative stress may be an interesting strategy for controlling the progression of the disease. Since 17ß-estradiol exerts neuroprotective functions and has proved beneficial effects on several mechanisms such as neuroinflammation, excitotoxicity, among others, we assessed whether the selective activation of the G protein-coupled estrogen receptor (GPER), characterized by being involved in rapid non-genomic actions of 17ßestradiol, can exert a neuroprotective effect associated with the modulation of oxidative stress. With this objective, we developed an in vivo study with mice injected with 6-OHDA, which were later submitted to subcutaneous or intranasal treatment with the GPER agonist, G1. We evaluated how the selective activation of the receptor can contribute to the reversion of oxidative stress. To this end, several behavioral tests were performed to evaluate motor function, such as Grip Test, Rotarod and Open Field Test, and relative mRNA levels of antioxidant enzymes were measured by real-time PCR (RT-PCR). From the behavioral tests, it was possible to conclude that the 6-OHDA-injection was not capable of affecting motor behavior, since the results obtained with the Rotarod test, and the total distance travelled obtained with the Open field Test did not present significant differences. On the other hand, it was possible to observe that the parameters related with anxious behavior were increased in animals injected with 6-OHDA, when compared with the control group. Therefore, it can be concluded that the toxin had no effect at the level of motor behavior, but induced changes in non-motor domains. Regarding the expression of antioxidant enzymes, although not significant, an increase in the mRNA levels of Gpx4 and Nrf2 was observed in 6-OHDAinjected mice. This increase suggests a protective mechanism aiming to limit oxidative stress. However, further studies are needed to confirm this hypothesis. Our results have shown effects exercised by the G1, when administered by the two delivery approaches. However, it was not possible to conclude whether the two types of G1 delivery have an antioxidant effect in the presence of a dopaminergic insult. In this sense, further studies would be necessary to confirm whether GPER activation is capable of modulating oxidative stress and whether this effect is related to its currently recognized neuroprotective effects.
O cérebro caracteriza-se por apresentar um elevado metabolismo, e contém várias substâncias facilmente oxidáveis, tais como aminas e lípidos, o que resulta numa exposição a elevados níveis de stress oxidativo. Foi demonstrado que na doença de Parkinson (DP), o stress oxidativo está correlacionado com a peroxidação lipídica, inflamação, disfunção mitocondrial e agregação da a-synucleína (a-syn). Isto demonstra que o stress oxidativo pode ser um dos desencadeadores da doença de Parkinson, por ser capaz de induzir uma série de mecanismos patogénicos característicos da doença, contribuindo de forma crucial para a sua progressão. Neste sentido, a identificação de mecanismos que ajudem a reduzir o stress oxidativo podem ser estratégias interessantes para o controlo da progressão da doença. Uma vez que o 17ß-estradiol foi classificado como neuroprotetor e já demonstrou efeitos benéficos em diversos mecanismos como neuroinflamação, excitotoxicidade, entre outros, fomos avaliar se a ativação seletiva do recetor de estrogénios acoplado à proteína G (GPER), caracterizado por estar envolvido em ações não genómicas rápidas do 17ßestradiol, pode exercer um efeito neuroprotetor associado à modulação do stress oxidativo na DP. Com este objetivo, desenvolvemos um estudo in vivo com murganhos injetados com 6-OHDA, que foram, posteriormente, submetidos a tratamento subcutâneo ou intranasal com um agonista do recetor, o G1. Assim, avaliámos de que forma a ativação seletiva do recetor pode contribuir para a reversão do stress oxidativo. Para isso, foram efetuados vários testes comportamentais para avaliar a função motora, como o Grip Test, o Rotarod e o Open Field Test, e foram medidos os níveis de mRNA de enzimas antioxidantes, por PCR em tempo real (RT-PCR). A partir dos testes comportamentais, foi possível concluir que a injeção da toxina não afetou o comportamento motor uma vez que os resultados obtidos no Rotarod, e distância total percorrida obtida no Open Field Test não mostraram diferenças significativas. Por outro lado, foi possível observar que a injeção com 6-OHDA aumentou os parâmetros relacionados com o comportamento ansioso. Desta forma, é possível concluir que a toxina não exerceu efeito ao nível do comportamento motor, porém, induziu alterações a nível não-motor. Relativamente à expressão das enzimas antioxidantes, observou-se um aumento, ainda que sem significância estatística, dos níveis de mRNA da Gpx4 e do Nrf2 em animais injetados com 6-OHDA. Este aumento, pode querer evidenciar um mecanismo de proteção desencadeado por estas enzimas para lidar com o stress oxidativo. No entanto, mais estudos seriam necessários para conseguir comprovar esta hipótese. Os nossos resultados evidenciaram efeitos exercidos pelo G1, quando entregue pelos dois tipos de administração. No entanto, não foi possível concluir se os dois tipos de entrega do G1 têm um efeito antioxidante na presença de um insulto dopaminérgico. Neste sentido, mais estudos seriam necessários para perceber se a ativação do GPER é capaz de modular o stress oxidativo e, se este efeito está relacionado com os seus efeitos neuroprotetores atualmente reconhecidos.
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40

Tavares, Ana Filipa Pereira. "In vitro testing of estrogen agonists for the evaluation of reactive oxygen species production in glioma cells." Master's thesis, 2014. http://hdl.handle.net/10451/38743.

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Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2014
Compelling evidence show that cell exposures to 17β-estradiol (E2) trigger intracellular reactive oxygen species (ROS) production. These species play an important role in both tumor development and responses to anticancer strategies and their accumulation in normal cells leads to the occurrence of numerous oxidative reactions which can cause overwhelming damages and promote cell apoptosis. Nevertheless, there is an elevated basal level of oxidative stress in cancer cells, which is balanced by their increased antioxidative capacity. This fact suggests cancer cells may be more susceptible to further oxidative stress than normal cells and strategies that explore these pathways would increase the lethality of anticancer agents. In this study, exposures of cancer cells to estrogen agonists are made and fluorescence techniques used in the attempt to lead cells to apoptosis by increasing their oxidative stress levels. These exposures are made using 13 estrogen previously-synthetized analogues and four different time points (1h, 2h, 6h and 24h). In the end, the results show that the tested compounds induce a rapid production of ROS but this is not a lasting effect and doesn’t affect cell viability. E2 is the compound with the highest and more stable levels of oxidative stress production.
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41

Gagliardi, Christina F. "Increased Body Weight in Adulthood Following a Peripubertal Stressor and Proposed Mechanism for Effects of Increased Adiposity on Estrogen-dependent Behaviors." 2014. https://scholarworks.umass.edu/masters_theses_2/86.

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Exposure to certain stressors during a sensitive period around puberty can lead to enduring effects on an animal’s response to estradiol. In estradiol-influenced behaviors, such as sexual receptivity, hippocampal-dependent learning and memory, depression-like behavior, and anxiety-like behaviors, exposure to a peripubertal stressor such as shipping stress or an injection of lipopolysaccharide (LPS) can eliminate or even reverse the normal response to estradiol. In addition to regulating these behaviors, estradiol play a role in the regulation of body weight. While some of the previous studies touched on short-term effects on body weight, no systemic long-term study of the effects of a peripubertal stressor on body weight, particularly without interruption by ovariectomy, have been undertaken. This paper introduces a hypothesis that proposes that increased adiposity following exposure to a peripubertal stressor leads to the changes to estrogen-dependent behaviors through altered levels of estrogens and changes to estrogen receptors. The first chapter examines body weight data collected during studies with other aims, and then proposes an experiment to test whether either of two peripubertal stressors results in increased weight gain and body weight. The following chapter proposes further experiments designed to determine the proximate mechanisms leading to weight gain following peripubertal stressors and the role of diet on weight gain. The final chapter proposes experiments to test the effects of adiposity on peripheral levels of testosterone, aromatase, estradiol, and estrone; central levels of estradiol and estrone; and estrogen receptors in the brain.
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42

Falconer, Erin Michelle. "Sex differences and the effects of estrogen on cell proliferation, cell death and behaviour due to acute and repeated predator odour stress in adult rats." Thesis, 2002. http://hdl.handle.net/2429/12461.

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Possible sex differences in response to predator odour exposure were examined in adult rats. The first study measured behaviour, cell proliferation, and survival in the dentate gyrus of adult males and females in response to acute and repeated trimethyl thiazoline (TMT, the main component of fox feces) or control odour exposure. Rats were injected with one of the cell synthesis markers bromodeoxyuridine (BrdU) or [³H] thymidine and perfused 24 hours (cell proliferation) after an acute TMT exposure or after 5 days (cell survival) of repeated TMT exposure. After acute exposure, cell proliferation and death were suppressed in TMT-exposed males compared to control males, but not in females. Repeated TMT exposure in males increased cell death and increased the survival of new cells born on Day 1 of exposure. Males initially expressed more defensive behaviours in response to TMT but this expression habituated after repeated TMT exposure. This habituation was concurrent with enhanced new cell survival, possibly indicating that learning enhanced new cell survival. In a second study, we assessed whether ovarian hormones altered the response to acute TMT exposure in females. Ovariectomized (OVX) females were given either a high dose of estradiol (EB) or a low dose of estradiol and progesterone followed by a high dose of estradiol (EB-P). TMT exposure did not affect cell proliferation in any group. However, hormone treatment affected the behavioural, hormonal, and cell death response to TMT. EB increased cell proliferation and decreased defensive behaviour whereas EB-P decreased cell proliferation and increased defensive behaviour. Thus, we demonstrated that pre-treatment with a low dose of estradiol and progesterone profoundly affected the behavioural and cellular response to later administration of estradiol. Taken together, acute TMT exposure suppressed both cell proliferation and death while repeated TMT exposure enhanced new cell survival and cell death in males. However, female rats did not show a change in cell proliferation, regardless of hormone condition, but OVX female rats exhibited increased cell death in response to acute TMT exposure. This is the first demonstration of a sex difference in cell proliferation and cell death in the adult dentate gyrus in response to stress.
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43

Gojska, Nicole. "Direct Steroidal Regulation and Inhibitory Mode of Action of Gonadotropin-inhibitory Hormone (GnIH or RFRP-3) in Immortalized Hypothalamic Cell Models." Thesis, 2013. http://hdl.handle.net/1807/65437.

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Fertility is dependent on the precisely orchestrated communication of an array of effectors within the reproductive axis, all of which impinge on gonadotropin-releasing hormone (GnRH) neurons. A novel reproductive inhibitor was identified in avian species and growing evidence suggests that the functional mammalian homologue, RFamide-related peptide-3 (RFRP-3 or GnIH) can inhibit GnRH neuronal activity and gonadotropin release. To date, the regulation and effects of RFRP-3 at the hypothalamic level are poorly understood. We established an Rfrp-expressing neuronal cell model to investigate the mechanisms of transcriptional regulation of the genes for RFRP and the RFRP receptor, GPR147 by dexamethasone and estradiol. We show that the RFRP system is a direct target for stress-associated transcriptional regulation. Further, employing a novel GnRH-secreting cell line, we report that GnRH neurons express Gpr147 and RFRP-3 represses the transcription of GnRH. These data further our understanding of the level and regulatory effects at which RFRP-3 modulates reproduction.
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44

Sultana, Zakia. "Increased oxidative damage and premature placental aging contribute to the aetiology of stillbirth." Thesis, 2018. http://hdl.handle.net/1959.13/1391445.

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Research Doctorate - Doctor of Philosophy (PhD)
Stillbirth is a neglected public health problem affecting more than two million women and families globally each year with devastating and long-lasting psychosocial and financial impact. Rates of stillbirth, even in high-income countries with access to optimal obstetric care, have remained static in the past two decades. The causes of, or associations with, stillbirth that have been identified clinically include fetal factors such as genetic/structural abnormalities and growth restriction, maternal factors such as preeclampsia and infections and placental factors such as abruption and placenta previa. However, no specific cause has been established for the majority of stillbirths at term, and the rate of this category of death rises drammatically as gestation progresses beyond 38 weeks. Taking into account the functional definition of aging that is an increase in the risk of death with time, and the existence of placental pathologies in the unexplained stillbirth pregnancies resembling aging in other organs, we hypothesise that premature placental aging may be the primary factor in the aetiology of unexplained stillbirth. Premature aging may occur when cells experience increased oxidative stress that causes damage to cellular macromolecules, including DNA, RNA and lipids, and alters protein expression patterns, especially those that are crucial for cellular survival and function. Therefore, the primary aim of this thesis was to investigate evidence that the placenta from late-gestation shows biochemical signs of oxidative damage and aging that would also be present in placentas associated with stillbirths. A further aim was to investigate the pathways that mediate the oxidative damage and aging in the placenta in pathologic pregnancies. We have shown that placentas from both late-term and stillbirth pregnancies show biochemical signs of aging in the form of increased DNA and lipid oxidation. Also, the expression of aldehyde oxidase 1 (AOX1), which is known to be involved in reactive oxygen species (ROS) generation and oxidative stress, is increased in placental tissues obtained from both late-gestation and stillbirth pregnancies. We tested the association of AOX1 in stillbirth pregnancy as an RNA sequencing study performed in our laboratory identified a significant increase in AOX1 mRNA in late-term placentas compared to term healthy placentas (unpublished). The demonstration of G-protein coupled estrogen receptor 1 (GPER1), a cell surface estrogen receptor, localisation on the apical surface of the normal placental syncytiotrophoblast and its role in the reduction of ROS generation and oxidative damage indicate that this receptor may be a critical step in the pathway of placental ROS induced oxidative damage. Using a placental explant and a cell line culture model, we then tested the pathways that regulate placental oxidative damage and aging. Results presented in this thesis revealed that growth factor removal resulted in placental oxidative damage, with impaired mitochondrial function, decreased expression of sirtuins (proteins that control aging), alteration of nutrient sensing mammalianTORC1, and energy sensing AMP activated protein kinase pathways, all the changes are known to be associated with oxidative damage and aging in other tissues. Inhibition of AOX1 or stimulation of estrogen activation at GPER1 resulted in the blocking of all the changes observed after removal of growth factors. Together, these findings support the hypothesis that placental oxidation is regulated by estrogen activation at the GPER1 and inhibition of AOX1 leading to the inhibition of ROS generation and oxidative stress. Our study identifies potential biomarkers of oxidative damage and aging in stillbirth placentas that raise the possibility that these biomarkers of placental oxidative damage and aging may be released into the maternal blood where they may have diagnostic value in predicting the fetus at risk for stillbirth. Treatment targeting AOX1 and/or GPER1 may arrest the oxidative damage in the placenta in pregnancies identified at risk and may lead to novel therapeutic strategies for delaying placental aging, as well as preventing stillbirth and other age-related adverse pregnancy outcomes.
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45

Hassan, Amani. "Effets de l'estradiol et du chargement mécanique sur la régulation de la POC5 et du récepteur ADGRG7 dans la scoliose idiopathique." Thèse, 2018. http://hdl.handle.net/1866/21839.

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