Dissertationen: „Placenta; transporter; transportér“

1

Russi, Rachel Mary. "The molecular regulation of placental zinc transporters." Thesis, University of Newcastle Upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402646.

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2

Peres, Kenya Costa [UNESP]. "Transporte placentário via cavéola na placenta de bovinos clonados e transgênicos." Universidade Estadual Paulista (UNESP), 2014. http://hdl.handle.net/11449/115903.

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Made available in DSpace on 2015-03-03T11:52:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-02-26Bitstream added on 2015-03-03T12:06:08Z : No. of bitstreams: 1 000809964.pdf: 1108463 bytes, checksum: 43fa89dc624ca99b382ecaa200b42518 (MD5) A utilização da transgenia com a proteína fluorescente verde (GFP) como marcador de células de origem fetal nas placentas de clones bovinos servirá de modelo inédito para estudo morfofisiológico e imunológico da interação materno-fetal, visto que possibilitará o seu mapeamento, diferenciando as células fetais das maternas. Tal modelo terá aplicação direta, principalmente porque estes são animais que apresentam problemas em relação ao seu desenvolvimento. Com o auxílio deste modelo, pretende- se verificar o transporte de substâncias entre a mãe e o feto via endocitose, pela imunolocalização das proteínas chamadas de caveolinas. Para tanto foram utilizados 06 bovinos clonados e 30 bovinos de inseminação artificial (IA) com idade até 90 dias de gestação, os quais tiveram seu desenvolvimento interrompido mediante abate humanitário das receptoras e ovariosalpingohisterectomia, com posterior recuperação do útero gestante. Foram coletados os placentônios e o cório. Uma parte das amostras foi recortada e fixada, por imersão, em solução de parafolmaldeído a 4% ou formoldeído a 10% em tampão fosfato de sódio (PBS) a 0,1M pH 7.4, solução de Zamboni (4% de paraformoldeído, 15% de ácido pícrico, em tampão fosfato de sódio a 0,1M pH 7.4), metacarn (60% de metanol, 30% de clorofórmio, e 10% de ácido acético glacial), para verificação da morfologia e realização de imuno-histoquímica para as proteínas caveolinas -1 e -2 (CAV -1 e CAV-2). As caveolinas -1 foram localizadas nos vilos fetais e maternos, mas sua marcação mais forte foi observada no estroma endometrial. As caveolinas -2 tiveram marcação positiva no trofoblasto e membrana corioalantoide, e, especificamente em célula trofoblástica gigante binucleada. Sendo assim, os resultados mostram que a proteína CAV-1 teve uma maior expressão em relação a proteína CAV-2 e que as proteínas CAV-1 e -2 são parte da composição das cavéolas, sendo . The transgenic application of green fluorecent protein (GFP) as fetal cell marker on cattle cloned placenta could provide an exclusive model for studying the morphologic and immunologic maternal-fetal interactions, providing information about its mapping, distinguishing the fetal from maternal cells. This model will have direct application, mainly because these are animals that present problems during its development. With this model's support, we intend to verify the substances transport between mother and fetus during endocytocis, through the immunolocalization of protein named caveolae. For these, we used 06 cloned bovine and 30 cattle samples of artificial insemination (AI) with 90 days of pregnancy, which had been their development interrupted by humanitarian slaughter of the recipient and recovery of the pregnant uterus. We collected the placentome and the chorion. A part of the samples will be cutted and fixed, by immersion, on a solution containing 4% of parafomaldehyde or 10% of formaldehyde on a sodium phosphate buffer (PBS) at 0,1M pH 7.4, Zamboni solution (4% of paraformaldehyde, 15% of picric acid, on sodium phosphate buffer 0,1M pH 7.4), metacarn (60% of metanol, 30% of chloroform, and 10% glacial acetic acid), for morphologic and immunohistochemistry verification for caveolinas proteins -1 and -2 ( -1 CAV and CAV- 2). The caveolinas -1 were found in fetal and maternal villi , but its strongest staining was observed in the endometrial stroma . The caveolinas -2 had positive staining in trophoblast and chorioallantoic membrane , and specifically in giant trophoblastic binucleated cell . therefore the results were compared between cloned cattle and from AI or natural mating, for assisting on detection of the reason of many placental alterations, embryonic losses, spontaneous abortion, post-natal mortality and large offspring syndrome on laboratory-manipulated animals. The result suggests that the proteins caveolins -1 and ...

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3

Peres, Kenya Costa. "Transporte placentário via cavéola na placenta de bovinos clonados e transgênicos/." Dracena, 2014. http://hdl.handle.net/11449/115903.

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Orientador: Flavia Thomaz Verechia Pereira Banca: Cristiana Andrighetto Banca: Vanessa Gomes Ueno Resumo: A utilização da transgenia com a proteína fluorescente verde (GFP) como marcador de células de origem fetal nas placentas de clones bovinos servirá de modelo inédito para estudo morfofisiológico e imunológico da interação materno-fetal, visto que possibilitará o seu mapeamento, diferenciando as células fetais das maternas. Tal modelo terá aplicação direta, principalmente porque estes são animais que apresentam problemas em relação ao seu desenvolvimento. Com o auxílio deste modelo, pretende- se verificar o transporte de substâncias entre a mãe e o feto via endocitose, pela imunolocalização das proteínas chamadas de caveolinas. Para tanto foram utilizados 06 bovinos clonados e 30 bovinos de inseminação artificial (IA) com idade até 90 dias de gestação, os quais tiveram seu desenvolvimento interrompido mediante abate humanitário das receptoras e ovariosalpingohisterectomia, com posterior recuperação do útero gestante. Foram coletados os placentônios e o cório. Uma parte das amostras foi recortada e fixada, por imersão, em solução de parafolmaldeído a 4% ou formoldeído a 10% em tampão fosfato de sódio (PBS) a 0,1M pH 7.4, solução de Zamboni (4% de paraformoldeído, 15% de ácido pícrico, em tampão fosfato de sódio a 0,1M pH 7.4), metacarn (60% de metanol, 30% de clorofórmio, e 10% de ácido acético glacial), para verificação da morfologia e realização de imuno-histoquímica para as proteínas caveolinas -1 e -2 (CAV -1 e CAV-2). As caveolinas -1 foram localizadas nos vilos fetais e maternos, mas sua marcação mais forte foi observada no estroma endometrial. As caveolinas -2 tiveram marcação positiva no trofoblasto e membrana corioalantoide, e, especificamente em célula trofoblástica gigante binucleada. Sendo assim, os resultados mostram que a proteína CAV-1 teve uma maior expressão em relação a proteína CAV-2 e que as proteínas CAV-1 e -2 são parte da composição das cavéolas, sendo . Abstract: The transgenic application of green fluorecent protein (GFP) as fetal cell marker on cattle cloned placenta could provide an exclusive model for studying the morphologic and immunologic maternal-fetal interactions, providing information about its mapping, distinguishing the fetal from maternal cells. This model will have direct application, mainly because these are animals that present problems during its development. With this model's support, we intend to verify the substances transport between mother and fetus during endocytocis, through the immunolocalization of protein named caveolae. For these, we used 06 cloned bovine and 30 cattle samples of artificial insemination (AI) with 90 days of pregnancy, which had been their development interrupted by humanitarian slaughter of the recipient and recovery of the pregnant uterus. We collected the placentome and the chorion. A part of the samples will be cutted and fixed, by immersion, on a solution containing 4% of parafomaldehyde or 10% of formaldehyde on a sodium phosphate buffer (PBS) at 0,1M pH 7.4, Zamboni solution (4% of paraformaldehyde, 15% of picric acid, on sodium phosphate buffer 0,1M pH 7.4), metacarn (60% of metanol, 30% of chloroform, and 10% glacial acetic acid), for morphologic and immunohistochemistry verification for caveolinas proteins -1 and -2 ( -1 CAV and CAV- 2). The caveolinas -1 were found in fetal and maternal villi , but its strongest staining was observed in the endometrial stroma . The caveolinas -2 had positive staining in trophoblast and chorioallantoic membrane , and specifically in giant trophoblastic binucleated cell . therefore the results were compared between cloned cattle and from AI or natural mating, for assisting on detection of the reason of many placental alterations, embryonic losses, spontaneous abortion, post-natal mortality and large offspring syndrome on laboratory-manipulated animals. The result suggests that the proteins caveolins -1 and ... Mestre

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4

Evseenko, Denis. "Regulation and functional significance of ATP binding cassette transporters in human placenta." Thesis, University of Auckland, 2008. http://hdl.handle.net/2292/2348.

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The aim of this project was to study ATP binding cassette (ABC) transporters in the human placenta, in particular their regulation and role in trophoblast differentiation and survival. The presence and localisation of four major placental drug transporters, multidrug resistance gene product 1 and 3 (MDR1 and 3)/ABC subfamily B members 1 and 4 (ABCB1 and 4), multidrug resistance associated proteins 1 and 2 (MRP1 and 2)/ABCC1 and 2 and breast cancer resistance protein (BCRP)/ABCG2 was initially studied in term human placenta, cultured primary trophoblast and BeWo and Jar trophoblast-like cell lines. Jar cells were found to be more similar to nondifferentiated cytotrophoblast with respect to their ABC protein expression profile, whereas BeWo cells more closely reflected differentiated syncytiotrophoblast. Treatment of primary term trophoblasts in vitro with cytokines (TNF- or IL-1) decreased expression and activity of apical transporters ABCB1/MDR1 and ABCG2/BCRP. Growth factors, on the other hand, increased BCRP expression and activity, while estradiol stimulated BCRP, MDR1 and MDR3 expression MDR1/3 functional activity. The ability of BCRP/ABCG2 to abrogate the apoptotic effects of TNF- and ceramides was studied in primary trophoblast and BeWo cells using pharmacological and molecular (siRNA) approaches. The results suggest that BCRP/ABCG2 contributes to the resistance of trophoblast cells to cytokine-induced (extrinsic) apoptosis, whereas its effects on apoptosis activated via the intrinsic mitochondrial pathway is minimal. This altered resistance was associated with increased intracellular accumulation of ceramides and reduced ability to maintain phosphatidylserine in the inner leaflet of the plasma membrane. A role for BCRP/ABCG2 in cell protection from differentiation-induced stressors was also demonstrated during the process of cell fusion associated with transient loss of plasma membrane lipid asymmetry. Finally, expression of BCRP/ABCG2 (and 9 other genes) was studied in 50 placentas from normal pregnancy and pregnancies complicated with fetal growth restriction (FGR). A marked reduction of BCRP/ABCG2 and MDR1/ABCB1 expression was observed in FGR placentas, while other transporter genes were unaffected. Collectively these data suggest that BCRP/ABCG2 and probably other ABC transporters may play a hitherto unrecognised survival role in the placenta, conferring a “stress resistance” to trophoblast cells.

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Hirst, Chloe. "Placental taurine transport in pre-eclampsia." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/placental-taurine-transport-in-preeclampsia(85a6b6e1-f0be-46f4-bec4-22c03183ff19).html.

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Pre-eclampsia (PE) is a serious disease affecting approximately 5% of pregnancies per annum. The disease etiology is complex but its origin lies in abnormal placental development and function. PE is associated with inflammation, increased nitrative stress and abnormal renewal of syncytiotrophoblast (STB), the transporting epithelium of the placenta. STB is renewed by cytotrophoblasts (CTBs) that proliferate, differentiate and fuse with STB and this is balanced by apoptosis. The amino acid taurine facilitates proliferation, differentiation and apoptosis in non-placental tissues. Taurine is also cytoprotective, protecting cells from damage by inflammatory cytokines. Taurine is transported from maternal blood into STB by the amino acid transporter TauT. In isolated STB membranes, TauT activity is inhibited by agents that nitrate tyrosine residues. This thesis tested the hypothesis that STB TauT activity is down-regulated in PE due to post-translational modification of TauT through tyrosine nitration which lowers intracellular taurine and contributes to altered STB renewal. Placentas were collected from normal pregnancy (NP) and PE (blood pressure >140/90mmHg after 20 weeks gestation in previously normotensive women plus proteinuria >300 mg/L in a 24-hour collection). STB TauT activity, measured as Na+-dependent uptake of 3H-taurine into placental villous fragments, was significantly lower in PE (n=24) compared to NP (n=44). Western blotting of membrane enriched homogenates showed that TauT protein expression (normalised to β-actin) was significantly higher in placentas from PE (n=8) compared to NP (n=9). The presence of nitrotyrosine residues (marker of nitrative stress) in placentas of women with PE and NP was assessed by immunohistochemistry (IHC). The intensity of STB nitrotyrosine staining was greater in PE placentas that had reduced TauT activity (n=8) than in NP (n=7). To determine the effect of nitrative stress on TauT activity and STB renewal, placental villous explants from NP were cultured (7 days; n=6) and treated with SIN-1 (1mM; days 5,6) to induce nitrative stress. STB nitrotyrosine (IHC) and TauT activity (3H-taurine uptake) was determined on day 7 and STB renewal was assessed by IHC for apoptosis (M30), proliferation (dual staining for Ki67 and the CTB marker E-cadherin) and STB integrity (cytokeratin 7). SIN-1 increased STB nitrotyrosine staining intensity compared to controls, confirming induction of nitrative stress. SIN-1 reduced STB TauT activity, increased apoptosis, reduced CTB proliferation and altered STB regeneration compared to control. To determine the effect of reducing intracellular taurine on STB renewal, villous explants were cultured for 7 days with 2.5mM β-alanine to competitively inhibit taurine uptake (n=6). At day 7, intracellular taurine, measured as the steady-state accumulation of 3H-taurine, was 15% of normal. STB turnover was assessed at day 7 as described above. β-alanine significantly increased apoptosis and altered STB regeneration compared to controls. Following statistical analysis all p <0.05.In conclusion, STB TauT activity was lower, and protein expression higher, in PE compared to NP. STB nitrotyrosine was elevated in PE and nitrative stress inhibited STB TauT activity and disrupted STB renewal in vitro. Reducing intracellular taurine also disrupted STB renewal in vitro. Overall the data support the hypothesis that post-translational modification of TauT by nitration inhibits TauT activity in PE. This reduces intracellular taurine which contributes to abnormal renewal of STB. Further work is needed (a) to confirm that TauT is nitrated in PE and that reduced STB TauT activity lowers intracellular taurine and reduces taurine delivery to the fetus and (b) to determine the mechanism/s by which taurine regulates CTB apoptosis and facilitates renewal of STB.

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Taylor, Louise. "Comparative analyses of ABC transporters and metabolising enzymes in human and rat placental models." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/comparative-analyses-of-abc-transporters-and-metabolising-enzymes-in-human-and-rat-placental-models(3daff296-0364-4e4b-89f8-337dac6dbf10).html.

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The placenta provides a protective barrier for the developing foetus during gestation. Physiological barriers including the placenta, liver, kidney, intestine and blood-brain barrier are known to express ATP-Binding cassette transporters (ABC transporters) and metabolising enzymes. These specialised proteins have the ability to transport or metabolise xenobiotics. There is evidence to suggest that ABC transporters and metabolising enzymes are located at the interface between the maternal and foetal blood supplies (a cell layer referred to as the syncytiotrophoblast) and therefore may help protect the foetus from harmful xenobiotics. During new compound development prenatal developmental toxicity testing forms an important part of safety assessment. In order to predict potential toxicity of a new chemical entity to humans, rodent and non-rodent species are currently used. This thesis investigates the rat and human placental barrier properties in order to help facilitate our knowledge of species differences and contribute to our understanding of the limitations of these surrogate models. The approaches taken include: genomic analyses using microarray data to compare the overall expression of ABC transporters and metabolising enzymes throughout gestation in both species, immunohistochemical techniques to localise transporters and metabolising enzymes in the rat placenta, and in vitro functionality assays of selected transporters performed in rat and human placental cell line models. The main findings have shown a similar mRNA expression level of ABCG2/BCRP (breast cancer resistance protein) throughout gestation in the rat and human, however different mRNA expression levels of other transporters (slco4a1/oatp4a1 in particular) and metabolising enzymes were also highlighted. Immunohistochemistry localised selected transporters to the syncytiotrophoblast region of the rat placenta (the interface of maternal and foetal circulations). Functional in vitro assays were successfully utilised in rat and human placental cell lines which showed functional ABCB1/P-gp in both species. Overall, these findings provide a genomic characterisation of the rat and human protective placental barrier properties and show transporter functionality in in vitro cell-based assays which will prove useful in prenatal and developmental toxicity tests. Alternatives to using animals have been explored by using functional in vitro assays which could potentially be implored during the new compound discovery phase. This could help to make animal testing more selective for given compounds and ensures the new chemical entity is being tested in the model closest resembling the human.

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Wang, Meng. "Enhancement of the Placental Transmission of Lopinavir Using a Transporter Targeted Prodrug Strategy." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3973.

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Lopinavir (LPV) is a potent protease inhibitor specific for HIV-1. However, LPV has poor placental penetration due to substrate activity for efflux transporter by P-glycoprotein (P-gp). Since fatty acid transporters are highly expressed in the placenta during pregnancy, we designed fatty acid ester prodrug of lopinavir as substrates of fatty acid transporter in order to improve their uptake into placenta. Seven dicarboxylic acid esters of lopinavir have been made in our lab. The structures were characterized by 1H-NMR, 13C-NMR, LC-MS/MS, HRMS, IR and melting points. After making the prodrugs, an LC-MS/MS method with high specificity and sensitivity, as well as simultaneous quantitative analyses of lopinavir and SLPV, GLPV and DLPV in the BeWo cells methanol extraction was established and validated. The uptake of prodrugs (SLPV, GLPV and DLPV) in the BeWo cells was then determined. GLPV has the highest uptake followed by SLPV and then DLPV. The results suggest that the carbon length of the promoiety may have a positive relationship with the uptake. Ideal prodrugs should be stable before they reach placenta and can be hydrolyzed in the placenta and/or in fetal plasma. We did a series of stability and hydrolysis studies in human tissue fractions. The results showed that GLPV and SLPV were very stable in HIC, HLC and human adult plasma. DLPV was stable in HIC, HLC, but can be hydrolyzed in human adult plasma. GLPV and SLPV cannot be hydrolyzed in either human placenta or fetal plasma, while DLPV can be hydrolyzed in both human placenta and fetal plasma. Anti-HIV activities study of prodrugs was also conducted. The results showed that the EC50 of three prodrugs (GLPV, SLPV and DLPV) are 0.86 μM, 0.84 μM and 0.05 μM, which are much lower than 50 μM (The active drug criteria for this assay). It suggests that prodrugs have apparently anti-HIV activity. DLPV has comparable apparent anti-HIV activity to LPV (<0.02 μM). After incubation with CEM-SS cells for 6 days, almost half of DLPV was hydrolyzed into LPV. Therefore, the high anti-HIV potent of DLPV may be due to the anti-HIV activity of generated LPV.

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Jobarteh, Modou Lamin. "The effect of prenatal nutritional intervention on placental nutrient transporter expression and feto-placental outcome in rural Gambian women." Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=225784.

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Iron and zinc deficiency during pregnancy is common among women in low-income nations. In such settings, prenatal nutritional intervention is encouraged to improve pregnancy outcome. The impact of the intervention on transporter proteins involved in fetal nutrient supply is unexplored. This study investigated gene expression of some transporter proteins involved in fetal nutrient supply in the placenta. In a trial in rural Gambia, pregnant women at <20weeks of gestation were randomised to 4 nutritional intervention arms: i) Iron and folic acid (FeFol), representing the usual care ii) Multiple micronutrients (MMN) iii) Protein energy (PE) iv) MMN and PE (PE+MMN). All the intervention arms contained 60mg iron and 400μg of folic acid. FeFol and MMN interventions were given in tablet format, whereas PE and PE+MMN were in food format (lipid-based nutrient supplement- LNS). Maternal blood samples collected at booking, 20 and 30 weeks of gestation were assessed for iron levels, and zinc levels measured only the later samples. Gene expression of proteins involved in fetal iron, zinc, amino acid and glucose transport were measured on placental samples collected at birth. LNS (PE and PE+MMN) intervention was associated with low maternal iron status in late pregnancy and increased placental mRNA expression of the primary iron-uptake protein, transferrin receptor 1(TfR1). Intervention arms with no supplementary zinc (FeFol and PE) had lower maternal plasma zinc levels and increased placental mRNA expression of intracellular zinc-uptake proteins, ZIP1, ZIP4 and ZIP8. Different nutritional intervention strategies are associated with changes in maternal iron and zinc status during pregnancy and corresponding changes in the gene expression of placental iron and zinc uptake proteins. This might suggest differential fetal intrauterine response to the interventions. Understanding the role of the placenta in the delivery of nutrients to the fetus is important when considering intervention strategies.

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Sivaprasadarao, A. "Studies on the transport and uptake of vitamin A by placenta." Thesis, University of Leeds, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384722.

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Vasilopoulou, Elisavet. "The role of thyroid hormones in placental development and the importance of the thyroid hormone transporter MCT8." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1146/.

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Thyroid hormones (THs) are important for fetoplacental development. Human intrauterine growth restriction (IUGR) is associated with malplacentation and reduced fetal circulating concentration of THs. The expression of the plasma membrane TH transporters MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 was characterised in human placental biopsies across gestation. The protein expression of MCT8 was increased in samples from severe IUGR compared with normal pregnancies. In vitro, triiodothyronine (T\(_3\)) decreased survival and increased apoptosis of IUGR compared with normal cytotrophoblasts, which was associated with increased MCT8 expression. In normal cytotrophoblasts, MCT8 upregulation decreased survival, whilst MCT8 silencing increased survival independently of T\(_3\). In the extravillous trophoblast-like cell line, SGHPL-4, T\(_3\) resulted in a significant increase in cell invasion when MCT8 was upregulated. Contrary to cytotrophoblasts, silencing MCT8 decreased apoptosis in SGHPL-4s independently of T\(_3\). In mice, fetal to placental weight ratio was decreased in male MCT8-null compared with wild-type embryos. These findings support the hypothesis that THs have an important role in fetoplacental development and that IUGR is associated with changes in TH transport and responsiveness of the placenta. Furthermore, they highlight the importance of MCT8, which impacts on placental cells via both T\(_3\)- dependent and independent mechanisms.

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Brett, Kendra Elizabeth. "Maternal Phenotype, Directly Measured Physical Activity and Associations with Placenta Nutrient Transport Related Gene Expression." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32514.

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The intrauterine environment plays an important role in fetal development and downstream health. Given the rise in maternal obesity and the incidence of babies being born large-for-gestational-age, research is needed exploring the mechanisms through which maternal obesity and health behaviours affect the delivery of nutrients to the fetus. This thesis includes three manuscripts in the pursuit of two objectives: 1) To determine whether there are changes in placenta nutrient transport-related gene expression in response to obesity, excess gestational weight gain, and variations physical activity and diet, and 2) To examine whether the Pregnancy Physical Activity Questionnaire is a reliable estimate of physical activity during the second trimester of pregnancy. In manuscript 1, we found that maternal obesity was not related to placenta nutrient transport-related gene expression, with the exception of lower placental mTOR expression in obese women who delivered male offspring, however, gestational weight gain was related to the gene expression of key proteins in the placenta. In manuscript 2, it was determined that the Pregnancy Physical Activity Questionnaire significantly overestimates physical activity and is not correlated with direct measures of activity and thus should not be used in future research. In manuscript 3, we found that physical activity and diet modify the expression of the genes involved in placenta nutrient transport. Meeting physical activity guidelines was associated with lower expression of a fatty acid transporter and higher expression of an amino acid transporter, while sugar intake was related to the expression of a glucose transporter. Together, the studies that make up this thesis suggest that there are numerous factors that may be contributing to placenta nutrient transport-related gene expression in humans and that future research on the placenta ought to include direct measures of physical activity and maternal diet, as well as account for gestational weight gain with respect to the guidelines and fetal sex.

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Carey, Erica Ashton Kayleigh. "AMP-Activated Protein Kinase Knockdown in Labyrinthine Trophoblast Cells Results in Altered Morphology and Function." Wright State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=wright1377417590.

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Hutchinson, Kelly Ann. "Assessing the Effect of Exercise During Pregnancy on Myokine Response and Placental Growth and Function In Vitro." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39808.

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Background: It is well established throughout the literature that regularly engaging in physical activity throughout pregnancy is associated with optimized health outcomes for both the mother and the fetus. The mediators and mechanistic pathways through which these observed exercise-induced outcomes are achieved are largely unknown. This thesis attempts to address this gap in knowledge. Methods: The objective of the first study was to develop an exercise protocol based on the recommendations from the ‘2019 Canadian guideline for physical activity throughout pregnancy’ and to subsequently evaluate the myokine response post-exercise. Pregnant (n=13) and non-pregnant (n=17) women performed a moderate-intensity bout of treadmill walking following which pre- and post-exercise serum for a panel of ten well-characterized myokines was analyzed. The objective of the second study was to evaluate whether acute and/or chronic exercise elicited changes in metrics of placental growth and development – thereby proposing possible mechanisms through which physical activity may be conferring health benefits to the fetus. Serum (pre- and post-exercise) collected from the first study was used to treat placental cell lines to assess the effect of acute exercise on cellular proliferation as well as nutrient transporter (GLUT1, SNAT1, FATP4) expression and localization. Term placental tissue collected from active (n=10) and non-active (n=10) participants in the PLACENTA study were used to evaluate the role of chronic exercise on changes in nutrient transporter (GLUT1, SNAT1, FATP4) expression and localization. Results: Pregnant women from the first study exhibited higher levels of four myokines post- versus pre-exercise: FGF21, EPO, BDNF and IL-15. As for the second study, BeWo cell lines treated with serum collected from pregnant women yielded higher GLUT1 expression compared to non-pregnant serum, independently of exercise. Lastly, FATP4 expression was found to be higher in term placentas of active compared to non-active pregnant women. Conclusion: This thesis identified four myokines that are elevated in the serum of pregnant women following a bout of acute exercise. The role of these myokines in pregnancy remains to be elucidated. Further, chronic and acute exercise are shown to alter expression of key placental macronutrient transporters.

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Crouse, Matthew Scott Pennell. "Effects of Maternal Nutrition on Fructose, Glucose, and Cationic Amino Acid Transporter Expression in Bovine Utero-Placental Tissues from Days 16 to 50 of Gestation." Thesis, North Dakota State University, 2016. https://hdl.handle.net/10365/28240.

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Poor Maternal nutrition has been implicated to reduce nutrient transport to the conceptus. Therefore, we hypothesized that maternal nutrition and day of gestation would impact mRNA expression of nutrient transporters GLUT1, GLUT3, GLUT5, GLUT14, CAT-1, CAT-2, and CAT-3 in beef heifers. Crossbred Angus heifers (n = 49) were bred via AI, assigned to nutritional treatment (CON = 100% of requirements for 0.45 kg/d gain and RES = 60% of CON) and ovariohysterectomized on d 16, 34, or 50 of gestation. Expression of CAT-2 was the only gene in any tissue to demonstrate a day × treatment interaction. Expression of nutrient transporters were not influence by nutritional treatment (P > 0.05); however, transporters were differentially expressed by day of gestation (P ≤ 0.05). We interpret these results to indicate that day, has a greater influence than a 40% global nutrient restriction on mRNA expression of nutrient transporters in bovine utero-placental tissues.

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Berveiller, Paul. "Cancer du sein pendant la grossesse : interactions des taxanes avec le trophoblaste humain par une approche ex vivo et in vitro." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T029/document.

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La survenue d’un cancer du sein découvert durant la grossesse est un événement dramatique compliquant entre 1/3000 et 1/10000 grossesses, ce qui en fait le cancer le plus fréquemment rencontré chez la femme enceinte. Sur le plan thérapeutique, certaines molécules anticancéreuses peuvent être utilisées, notamment les taxanes (paclitaxel et docétaxel). Si les études cliniques rétrospectives isolées semblent plutôt rassurantes, les données concernant leur passage transplacentaire sont encore fragmentaires. Quant à leurs effets sur le placenta humain et plus particulièrement sur la fonction de transport placentaire, ils sont pour l’heure inconnus. Nos objectifs étaient de 1) dresser une cartographie de l’expression génique physiologique des différents transporteurs placentaires de médicaments en utilisant un modèle de culture primaire trophoblastique, 2) d’apprécier le passage transplacentaire comparatif des taxanes et leur accumulation placentaire en utilisant le modèle du cotylédon perfusé, 3) d’étudier plus particulièrement les effets du paclitaxel sur le placenta humain et notamment sur l’expression des transporteurs de médicaments, en utilisant en plus des modèles mentionnés, les cotylédons de patientes ayant été traitées par paclitaxel durant leur grossesse. Nos études ont tout d’abord permis de dresser une cartographie originale de l’expression physiologique de plus de 80 transporteurs placentaires de médicaments, et ce comparativement entre le début et la fin de la gestation. De plus, nos expériences ont montré que le passage transplacentaire des taxanes était faible et comparable entre les deux molécules, et que celles-ci semblaient s’accumuler dans les cotylédons placentaires. Enfin, nous avons pu mettre en évidence un effet significatif du paclitaxel sur le placenta humain, notamment sur la modulation de certains transporteurs de médicaments The occurrence of breast cancer during pregnancy is a dramatic event reaching roughly 1/3000 to 1/10000 pregnancies, this type of cancer being the most frequent in pregnant women. Regarding therapeutic options, some anticancer agents may be used, especially taxanes (paclitaxel and docetaxel). If most of retrospective data appear to be reassuring, little is known regarding their transplacental transfer. Moreover, to our knowledge, potential effects of taxanes on human placenta, especially on placental transport function are unknown. Our aims were to 1) provide a transcriptional expression cartography of various placental drug transporters throughout pregnancy, using primary trophoblast culture model, 2) assess the comparative transplacental transfer of taxanes and their accumulation in cotyledons, using the perfused placental model, 3) assess potential effects of paclitaxel on human placenta, especially on drug transporter expression, not only using above-described models, but also cotyledons from pregnant-cancer patients treated with paclitaxel during pregnancy. Here, we finally provided an original transcriptional cartography of various drugs transporters in human normal placenta all along pregnancy. Moreover, we found a low and comparable transplacental transfer of paclitaxel and docetaxel that led to a moderate accumulation in cotyledons. Finally, we evidenced a significant effect of paclitaxel on human placenta, especially by modulating drug transporter expression

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Ferré, Dolcet Lluis. "Expression of cellular transporters of water and monosaccharides in the uterus and the placental transference zone in different gestational and non-gestational phases in the queen." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/400409.

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La placenta está considerada como el órgano principal encargado del transporte de solutos y nutrientes entre madre y feto. Por su característica función, durante la gestación, tanto el útero como la placenta sufren diversos cambios estructurales para la preparación del endometrio para la futura implantación y desarrollo fetal. El balance hidrológico y el metabolismo glucídico son mecanismos esenciales para la preparación del epitelio y del estroma para la implantación del embrión, estando también involucrados en el desarrollo fetal proporcionando una correcta nutrición al feto en desarrollo. Estos mecanismo son llevados a cabo mediante transportadores de agua denominados acuaporinas (AQPs) y transportadores de glucosa (GLUTs). Tanto las AQPs como los GLUTs han sido descritos ampliamente en el aparato reproductor femenino en una gran variedad de especies. Los objetivos de este estudio fueron: • Determinar la expresión y localización de las AQPs 1, 2, 3 y 8 además de los GLUTs 1 y 3 en el útero y la zona de transferencia placentaria de las gatas. • Determinar una posible correlación de estas proteínas con los niveles séricos de progesterona. • Determinar una posible correlación de estas proteínas entre ellas a diferentes fases sexuales y gestacionales. • Determinar variaciones en la actividad de la AQP2 durante la gestación de la gata mediante la evaluación de cambios en su fosforilación de residuos de tirosina. Las gatas se dividieron inicialmente en dos grupos: gestantes y no gestantes. Tras ello, las gatas gestantes se dividieron en 30, 40, 50 y 60 días de gestación según el diámetro de la vesicular embrionaria. Las gatas no gestantes se dividieron entre ovuladas y no ovuladas según sus niveles séricos de progesterona. Las biopsias realizadas de útero y zona de transferencia placentaria se evaluaron mediante técnicas de inmunoblotting e inmunohistoquímica. Las técnicas de inmunoblotting e inmunohistoquímica revelaron la expresión de las AQPs 1, 2, 3, 8 en las células epiteliales del endotelio laminar y glandular además de en la zona de transferencia placentaria durante las diferentes fases sexuales y gestacionales. Las AQPs 2, 3 y 8 se expresaron en las capas coriónicas, mientras que la AQP1 no mostró ninguna expresión en las células del córion, contrariamente a lo anteriormente descrito por otros autores. Estas AQPs no mostraron cambios estadísticamente significativos durante las diferentes fases sexuales y gestacionales. Sin embargo, se observaron cambios en la localización de las AQPs 2 y 8 relacionados con los niveles séricos de progesterona. Así, cuando los niveles de progesterona sérica eran bajos (<1ng/ml), éstas AQPs sólo mostraron su localización en la membrana citoplasmática de las células endoteliales del epitelio laminar y glandular. Cuando los niveles séricos de progesterona eran altos (>2ng/ml), éstas acuaporinas se encontraron tanto en la membrana citoplasmática como repartidas por todo el citoplasma del epitelio laminar y glandular. Además, la actividad de las AQP2 no estaba regulada por la fosforilación de tirosina. Los GLUTs 1 y 3 también estaban presentes tanto en el epitelio laminar como en el epitelio glandular del endometrio y en las capas coriónicas de la zona de transferencia placentaria. No se encontraron cambios estadísticamente significativos en su expresión a lo largo de las distintas fases sexuales y gestacionales. Finalmente, la AQP2 mostró una correlación positiva y significativa con los niveles séricos de progesterona, mientras que la AQP1 y el GLUT3 mostraron una correlación negativa con los niveles de progesterona. Además, las AQPs 1 y 3 mostraron una correlación negativa y significativa entre ellas en todas las fases evaluadas. En conclusión, éste estudio confirma la presencia de las AQPs 1, 2, 3, 8 y de los GLUTs 1 y 3 en el endometrio y en la zona de transferencia placentaria de la gata a lo largo de diferentes fases sexuales y gestacionales como ha sido previamente descrito en otras especies a pesar de ciertas diferencias específicas. The placenta is considered to be the major organ for the regulation of the exchange of solutes and nutrients between the conceptus and the dam. Because of this function, during pregnancy, both uterus and placenta concomitantly undergo several structural changes to prepare the endometrium for further implantation and fetal development. Fluid balance and glucose metabolism are essential mechanisms to prepare the epithelium and stroma for embryo implantation and are also involved in the fetal development by providing nutrition to the developing conceptus. These mechanisms are accomplished by water transporters, named aquaporins (AQPs), and glucose transporters (GLUTs). AQPs and GLUTs have been widely studied in the female reproductive tract of many species. The aims of this study were: • To determine the expression and location of AQPs 1, 2, 3 and 8 and GLUTs 1 and 3 in the queen uterus and placental transference zone. • To determine a possible correlation between the expression of these proteins with serum levels of progesterone. • To determine a possible correlation of these proteins between them at different sexual and gestational phases. • To determine variations in AQP2 activity during queen pregnancy by evaluating the changes in the tyrosine phosphorylation levels of AQP2. Queens were divided firstly into two groups: pregnant and non-pregnant queens. After that, pregnant queens were divided into 30, 40, 50 and 60 days of pregnancy according to the diameter of the fetal vesicle. Non-pregnant queens were divided into ovulated and non-ovulated queens according to serum levels of progesterone. Samples from endometrium and placental transference zone were evaluated by immunoblotting and immunohistochemistry techniques. AQPs 1, 2, 3, 8 were present in the cells from both endometrial luminal and glandular epithelia and the placental transference zone during different sexual and gestational phases by western blotting and immunochemistry. AQPs 2, 3 and 8 have been located in the chorionic layers while AQP1 was absent, contrary to what has been described by other authors. No statistically significant changes in AQPs expression was observed at the different sexual and gestational phases. However, changes in the location of AQP2 and 8 related to serum progesterone levels were observed. Thus, when serum levels of progesterone were low (<1ng/ml), these AQPs were located only in the cell membrane of luminal and glandular epithelia. When serum progesterone were high (>2ng/ml), these APQs were in both cell membrane and cytoplasm from luminal and glandular epithelia. Moreover, AQP2 activity was not regulated by tyrosine phosphorilation. GLUT1 and 3 were also present in luminal and glandular epithelial cells from the endometrium and in the chorionic layer of the placental transference zone. No statistically significant changes in GLUTs expression were observed among the different sexual and gestational phases. Finally, AQP2 showed a positive correlation with progesterone levels, while AQP1 and GLUT3 showed a negative correlation with serum progesterone levels. In addition, AQP1 and AQP3 showed a negative correlation between them in the evaluated phases. In conclusion, the present study confirms the presence of AQPs 1, 2, 3, 8 and GLUTs 1, 3 in the queen endometrium and placental transference zone across different sexual and gestational phases as it has been previously described in other species, although with some specific differences.

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SCHMID, KARA E. "ENDOGENOUS AND EXOGENOUS SOURCES OF CHOLESTEROL DURING FETAL DEVELOPMENT." University of Cincinnati / OhioLINK, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1061304521.

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Daoud, Georges. "Implication des protéines cytoplasmiques liant les acides gras dans le transport de l'acide linoléique et identification des mécanismes impliqués dans la différenciation des cellules placentaires humaines /." Montréal : Université du Québec à Montréal, 2006. http://accesbib.uqam.ca/cgi-bin/bduqam/transit.pl?&noMan=24634896.

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Rigourd-Rey, Virginie. "Evaluation de l'implication du gène STOX1 dans la pathologie placentaire." Paris 11, 2010. http://www.theses.fr/2010PA11T007.

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La PE est définie par une hypertension significative apparaissant au-delà de 20 semaines de grossesse associée à une protéinurie. C'est une pathologie fréquente (5-10% des grossesses) responsable d'une forte morbidité et mortalité materno-fœtale (éclampsie, hématome rétro-placentaire, prématurité induite, RCIU. . . ). La physiopathologie de la PE reste mal connue. Récemment, par clonage positionnel, le premier gène de prédisposition à la PE, STOX1 en 10q22 a été identifié. Le but de ce travail est d'évaluer le rôle de STOX1 et de ses cibles moléculaires dans la cascade complexe de la physiopathologie de la PE. Nous avons mené une analyse du transcriptome de cellules de type JEG-3 surexprimant STOX1, que nous avons créé. Cette étude a permis de mettre en évidence 2500 gènes modifiés par la surexpression du facteur transcriptionnel STOX1 qui ont pu être classés en 30 clusters fonctionnels. Ces voies sont directement impliquées dans la physiopathologie de la PE et des résultats préliminaires d'études fonctionnelles à partir de notre modèle cellulaire tendent à confirmer l'implication de STOX1 dans : la réponse à l'hypoxie ou au stress oxydatif, l'implantation, le développement précoce et la différenciation du placenta et l’interaction immunologique mère-fœtus. Au cours de l'année 2007, trois articles ont remis en question l'implication de STOX1 dans la PE. Nous pouvons grâce à nos résultats réhabiliter STOX1 comme gène candidat dans la PE et sommes en train d'envisager un modèle de souris transgéniques surexprimant STOX1. Ceci permettrait d'aller au-delà des modèles in vitro de PE. Créer un modèle in vivo de PE est un tremplin pour le décryptage de la PE mais surtout pour l'identification de nouveaux moyens de dépistage et de traitement quasi inexistants à l'heure actuelle. En conclusion, l'utilisation de l'outil génomique à haut débit dans la PE a permis d'affiner les connaissances physiopathologiques sur la PE et trace de nouvelles voies de recherche dans les domaines du diagnostic et des applications thérapeutiques Preeclampsia (PE) is defined by a significant high blood pressure appearing beyond 20 weeks of pregnancy associated with a proteinuria. It is a frequent pathology occurring in 5-10 % of the pregnancies, responsible for a strong morbidity and mortality materno-fœtale (eclampsia, placenta abrupto, prematurity, intra uterin growth restriction. . . ). The physiopathology of PE remains badly known. Recently, the first gene of predisposition in PE, STOXl 10q22 has been identified by positional cloning. The purpose of this work is to estimate the role of STOX1 and its molecular targets in the complex physiopathology of PE. We analysed the transcriptome of type JEG-3's cells over expressing STOX1 which we created. This study using micro array technology brought to light 2500 genes modified by the over expression of the transcriptionnal factor STOX1. Those have been classified into 30 functional clusters. These axis are directly involved in the physiopathology of PE. Our preliminary results of functional studies from our cellular model tend to confirm the implication of STOX1 in: i) the answer to the hypoxie or to the oxydatif stress, ii) the setting-up, the early development and the differentiation of the placenta and iii) the immunological interaction mother-foetus. During year 2007, three articles questioned the implication of STOX1 in PE. We thus rehabilitated STOXl as gene candidate in PE and therefore we envisaged a model of transgenic mice over-expressing STOX1. This allowed us to go beyond the in vitro models of PE. To create an in vivo model of PE is a means for the deciphering of this complexe disease and especially for the identification of new almost non-existent means of screening and treatment at the moment. In conclusion, the use of the genomic tool in PE allowed to refine the physiopathological knowledge on PE and to experiment new ways of research in the demains of the diagnosis and the therapeutic applications

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Lagrange, Fabrice. "Influence de la stéréosélectivité des antiinflammatoires non stéroi͏̈diens sur leur passage transplacentaire et leur distribution articulaire : application au kétoprofène." Bordeaux 2, 2000. http://www.theses.fr/2000BOR28777.

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Kučerová, Veronika. "Hodnocení exprese vybraných ABC transportérů v placentě." Master's thesis, 2021. http://www.nusl.cz/ntk/nusl-446181.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Veronika Kučerová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: PharmDr. Lenka Ťupová, Ph.D. Title of diploma thesis: Study on expression of selected ABC transporters in placenta The placenta is a temporary organ through which the fetus is supplied with nutrients and oxygen from the mother's blood and conversely waste substances are transferred into the mother's blood during pregnancy. Substance transfer through the placenta is a complex process controlled by a number of physiological mechanisms, including passive diffusion, facilitated diffusion or active transport, which is realized by activity of membrane transporters with energy consumption. Presence of active ABCs efflux transporters in the placenta has been known for a long time and their function is associated primarily with limiting the entry of harmful substances into the placenta and further into the fetus, thus contributing to its protection. Among the best described transporters belong P-glycoprotein (MDR1/ABCB1), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance protein 2 (MRP2/ABCC2), whose expression has been confirmed in the apical membrane of the placental syncitiotrophoblast facing...

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Dudičová, Simona. "Vliv stimulace placentárních buněk in vitro a ex vivo na expresi vybraných ABC a OATP transportérů." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-437879.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Simona Dudičová Supervisor: Assoc. Prof. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: The effect of in vitro and ex vivo placental cells stimulation on expression of selected ABC and OATP transporters The placenta is an organ that plays a key role throughout pregnancy for proper fetal development. One of the important functions provided by the placenta is the transport of substances between the mother and the fetus. This transfer of substances enabled mainly by membrane transporters, which are located on the apical and basal membranes of the syncytiotrophoblast. During various physiological or pathological changes in the human body, their expression and amount can vary significantly. Inflammatory reactions that may occur during pregnancy are also related to these changes, and therefore we have addressed this issue and believed that this condition may alter the expression of placental transporters. The aim of this work was to investigate the changes in the expression of membrane transporters using placental cells on BeWo cell lines and placental villous explants that were stimulated by pro-inflammatory mediators. The change in the expression of individual ATP-binding cassettes,...

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Michalská, Martina. "Exprese vybraných membránových transportérů v placentách těhotných žen s diagnostikovanou předčasnou rupturou plodových obalů." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-397867.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Martina Michalská Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Expression of selected membrane transporters in placentas of pregnant women diagnosed for preterm rupture of membranes Placenta is a key organ for pregnancy maintenance. One of its main functions is transport of compounds between mother and her fetus. The transplacental penetration is ensured due to membrane transporters that are present in the apical or basal side of trophoblast. Their expression level is affected by many physiological and pathological factors, among others it can be influenced by infection and inflamatory reaction. Inflammation is also one of the risk factors of preterm deliveries and it can be therefore assumed that these pathological states are accompanied by changes in expression of placental transporters. This study was performed using 51 placentas obtained from Faculty hospital in Hradec Králové from women who underwent preterm delivery and on 15 placentas delivered in term. The study employed quantitative RT-PCR approach. The mRNA expression of membrane transporters ABCB1, ABCG2, OATP1A2, OATP1B3, OATP2A1, OATP2B1, OATP3A1, OATP4A1 was assessed and the results were compared to...

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Umanová, Barbora. "Exprese a funkce placentárních lékových transportérů ve zdraví a nemoci." Master's thesis, 2020. http://www.nusl.cz/ntk/nusl-411912.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Barbora Umanová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Expression and function of placental drug transporters in health and disease There are many physiological changes during pregnancy. Placenta is a crucial organ which mediates exchange of nutrients, metabolites and respiratory gases, provides endocrine functions and fetal protection. A pregnant woman and her fetus may be exposed to various potentially harmful substances during pregnancy, including drugs that may endanger fetal health. Protection of the fetus from xenobiotics is enabled by drug transporters. Drug transporters are membrane proteins expressed in most tissues of the human body. In the placenta, they are localized in the placental syncytiotrophoblast and occur also in the endothelial cells of the fetal vessels. They belong into two large superfamilies of transporter proteins: ATB-binding cassette (ABC) and solute carrier (SLC). While ABC transporters mediate exclusively efflux of their substrates, SLC are predominantly influx transporters. Therefore, these transport proteins play a key role in the disposition of drugs, some of which facilitate drugs entry into a fetus, and others actively...

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Ťupová, Lenka. "Interakce vybraných antiretrovirálních léčiv a metylrtuti s membránovými transportéry placenty." Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-436154.

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Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Lenka Ťupová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of selected antiretroviral drugs and methylmercury with placental membrane transporters. Pregnant women are especially in developed countries exposed to high amount of various xenobiotic including environmental pollutants and drugs. Antiretroviral therapy (ART) is administered to HIV positive pregnant women for the purpose of prevention of HIV mother- to-child-transmission. Pharmacokinetics of many antiretrovirals is limited or enhanced by activity of ATP-binding cassette (ABC) or Solute carrier's transporters, of which many are expressed also in placental tissue. ART therapy usually consists of combination of 3 - 4 antiretroviral drugs, thereby leading to higher risk for development of drug-drug interactions on ABC and SLC transporters. In this study we described influence of non-nucleoside reverse transcriptase inhibitors etravirin and rilpivirin on BCRP- and MDR1-mediated transport of tenofovir disoproxil fumarate (TDF) and/or abacavir. Etravirin showed potent inhibition of BCRP transporter significantly changing transport of both, TDF and abacavir, across monolayers of MDCKII-BCRP...

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Currie, Margaret J. (Margaret Jane). "Regulation of glucose transporters in sheep placenta." 2001. http://hdl.handle.net/2292/3090.

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Transplacental glucose transport is vital to fetal growth. Although the presence of glucose transporter-1 (GLUT1) and GLUT3 has been demonstrated in mammalian placenta, the factors regulating these genes remain unclear. Therefore, the overall aim of these studies was to clone ovine GLUT1 (oGLUT1) and oGLUT3 cDNAs, and to use these to investigate gene expression during ovine placental development and function. Ovine GLUT1 (~2.2 kb) and oGLUT3 (483 bp) cDNAs were isolated and cloned. Sequence analysis demonstrated that oGLUT1 showed high homology (97 - 99%) with other mammalian species, whereas oGLUT3 did not (84 - 88%). Northern analysis demonstrated that oGLUT1 mRNA abundance increased from d 45 to d 120 of gestation, then decreased towards term (d 145 ± 2), whereas oGLUT3 mRNA abundance increased throughout gestation. Western analysis showed oGLUT1 protein levels increased during late gestation, indicating post-transcriptional regulation of oGLUT1. Localisation experiments revealed spatio-temporal differences in ovine placental GLUT expression. In early gestation (d 45), oGLUT1 protein was restricted to fetal trophoblast cells. By mid gestation oGLUT1 immuno-signal was predominantly localised to maternal villous and endometrial tissue. By late gestation oGLUT1 mRNA was most strongly localised to maternal syncytiotrophoblast and villous tissue, whereas oGLUT3 was predominantly localised to fetal trophoblast cells. Placental oGLUT expression was regulated differently by acute (3 - 8 h) versus long-term (>6 d) alterations in late gestation maternal glucose supply. No evidence was found for regulation of placental oGLUT gene expression by long-term maternal undernutrition, but oGLUT1 and oGLUT3 mRNA and oGLUT1 protein were elevated by short-term (24 - 48 h) maternal hypoglycemia. Acute maternal hyperglycemia transiently increased oGLUT1 and oGLUT3 mRNA abundance, whereas oGLUT1 protein (but not mRNA) levels increased after long-term maternal hyperglycemia. Infusion studies provided no conclusive evidence for regulation of placental oGLUTs by long-term administration of growth hormone (GH) or insulin-like growth factor-1 (IGF-1) to the late gestation fetus. Following acute (4 h) fetal IGF-1 infusion, placental oGLUT3 mRNA abundance was greater in growth restricted (placental embolisation) than in normal fetuses, although the reason for this difference remained equivocal. This thesis describes isolation, cloning and sequence analysis of oGLUT1 and oGLUT3 cDNAs. These studies confirmed the presence of GLUTI and GLUT3 mRNA in ovine placenta, and demonstrated ontogenetic and nutritional regulation of placental oGLUT1 and oGLUT3. In addition, these results indicated that regulation of placental oGLUTs may occur at both transcriptional and post-transcriptional levels.

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Dvořáková, Marie. "MRP transportní proteiny v placentě." Master's thesis, 2008. http://www.nusl.cz/ntk/nusl-292542.

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The MRP mebrane proteins, which belong to the ABC transporter family, comprise currently 9 members. The MRP transport proteins are expressed in various tissues of the organism, including placenta. The major physiological role of the multidrug transporters is the transport of many endogenous and exogenous compounds, including drugs, across the cell membrane. This thesis summarizes up to date information concerning expression and function MRP transporters in placenta a and in other tisssues in organism. Only five MRP transporters have been detected in placenta, namely MRP1, MRP2, MRP3, MRP5 a MRP8. Expression of all this proteins in placenta changes with progress of the pregnancy. MRP transporters help to protect fetus from potentially toxic substances, on the other hand some of them can facilitate the passage of substances across placenta. Some MRPs possess specific physiological functions in placenta. For example, MRP1 influences apoptosis, MRP5 participates in NO-dependent vasodilatation in fetal vessels.

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Matiašková, Zuzana. "Role vybraných ABC a SLC transportérů v přestupu maraviroku přes buněčné membrány: vliv na transport v placentě." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-397868.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and toxikology Student: Zuzana Matiašková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Role of selected ABC and SLC transporters in transmembrane permeability of maraviroc: effect on transport in placenta Antiretroviral drug maraviroc is an inhibitor of CCR5-trophic HIV virus and belongs to the group of entry inhibitors. Nowadays, maraviroc is administered as part of combination antiretroviral therapy (cART) primarily in adults, children over the age of two and pregnant women to reduce the risk of transmission of HIV to the fetus. The knowledge of interactions of maraviroc with drug transporters in placenta is crucial for optimizing the therapy during pregnancy, both in terms of efficacy and potential adverse effects. Maraviroc is known substrate of ABCB1 transporter, which plays a protective role to the fetus by its efflux activity in the apical membrane of trophoblast. However, the results of recent study employing dually perfused human placenta suggest involvement of other transport mechanisms in the maraviroc transplacental pharmaocokinetics, especially those operating in the opposite direction to ABCB1. The aim of this study was to evaluate in vitro studies whether, besides ABCB1,...

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Lalinská, Anežka. "Studium interakcí antiretroviálního léčiva tenofoviru a jeho proléčiva tenofoviru disoproxil fumarátu s placentárními nukleosidovými transportéry." Master's thesis, 2018. http://www.nusl.cz/ntk/nusl-382786.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Anežka Lalinská Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of interactions of antiretroviral drug tenofovir and its prodrug tenofovir disoproxil fumarate with placental nucleoside transporters Tenofovir (TFV) in the form of ester prodrug tenofovir disoproxil fumarate (TDF) is an essential part of combination antiretroviral therapy. It is often used in the prevention of perinatal HIV transmission. However, precise mechanism(s) involved in transfer of TFV/TDF from mother to fetus are not described in detail. Since these drugs are nucleoside analogues, there is a possibility that the mechanisms of their transplacental passage might include nucleoside transporters (NTs), either equilibrative or concentrative (ENTs/CNTs). The aim of the diploma thesis was to investigate the role of placental NTs in membrane transfer of TFV and TDF. To address this issue, we performed in vitro accumulation in the BeWo cell line derived from placental choriocarcinoma. By evaluating experiments, we found out that both TFV and TDF might not be substrates of NTs, thus the role of these transporters in TFV/TDF placental pharmacokinetics was not confirmed. Therefore, the drug-drug interactions on NTs...

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Křečková, Veronika. "Role lékových transportérů v placentárním přestupu entekaviru." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-397928.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Křečková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Role of drug transporters in placental transfer of entecavir Entecavir (ETV), an analogue of guanosine, is a highly efficient anti-hepatitis B antiviral drug. It is the first-line therapy for both adults and children. Its use in pregnancy is limited due to a number of factors, including lack of data on placental pharmacokinetics. The placental transition of drugs is frequently controlled by drug transporters. ATP-binding (ABC) transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or multidrug resistance-associated protein 2 (MRP2) localized in the apical membrane of syncytiotrophoblast and pumping their substrates in the feto-maternal direction belong to most significant determinants of placental pharmacokinetics. Moreover placental transport of nucleoside-derived drugs can be affected by the activity of nucleoside transporters (NTs); equilibrative nucleoside transporters (ENTs) mediate facilitated diffussion, while the concentrative nucleoside transporters (CNTs) control active influx of their substrates. The aim of the diploma thesis was to describe the role of P-gp, BCRP, MRP2 and NTs (ENTs and...

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Jirásková, Lucie. "Interakce membránových transportérů s léčivy v placentě a duktálním adenokarcinomu pankreatu." Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-415556.

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Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Lucie Jirásková Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of doctoral thesis: Interactions of membrane transporters with drugs in the placenta and pancreatic ductal adenocarcinoma Membrane transporters are found throughout the body, where they are responsible for many vital functions. Important representatives of membrane transporters are P-glycoprotein (ABCB1), Breast cancer resistance protein (ABCG2) and multidrug resistance-associated protein 2 (ABCC2) belonging to the ATP-biding Cassette (ABC) family. Nucleoside transporters belonging to Solute Carriers family (SLC) transporters represent another important group. It has been well evidenced that these transporters also affect drug disposition and contribute to tumor resistance to anticancer therapy. Over working on this dissertation thesis, we investigated the mentioned transporters (with special focus on nucleoside transporters) in complex fashion. We described the expression profile of nucleoside transporters in the placenta at different stages of gestation. We also examined whether the expression of nucleoside transporters changes depending on the degree of differentiation or can be affected epigenetically, and we...

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Schönwälderová, Denisa. "Principy transportu léčiv přes placentu: nové aspekty pro farmakoterapii v těhotenství." Master's thesis, 2009. http://www.nusl.cz/ntk/nusl-279067.

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7.SUMMARY After thalidomide-induced birth defects affair, the view of uterus as pharmacologically unconquerable site dramatically changed. Subsequently it was accepted that any chemical substance permeates across the placenta. As there was a continuing need for many mothers to continue to receive medications for chronic disease states, extensive research was launched to gain an appropriate rationale. Progressive investigation of placental barrier compounds allowed the emergence of in vitro and in vivo models, which enabled particularly drug transport studies. Syncytiotrophoblast plays an important role as a rate-limiting component of the barrier. Detailed understanding of pharmacokinetic changes that occur during gestation offered a rationale for pharmacotherapy in pregnancy (large charged molecule, excessive protein-binding, short elimination half-life, volume of distribution, fetal-maternal serum pH gradient). The mechanism of passive diffusion is most important way of drug transport. Perfusion studies clarified the crucial role of active efflux transporters, members of ABC protein family, namely P-glycoprotein, multidrug resistence-associated proteins a ABCG2. As P- gp was first to be discovered, is the most studied until now. Its substrates and inhibitors are well defined and their interactions are...

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Wu, Jing-Shan, and 吳菁山. "Effects of phenobarbital on human placental glucose transporters type I and type III." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/42617912076741821162.

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碩士 國立臺灣大學 藥學研究所 95 The sodium-independent facilitated glucose transporters, GLUT1 and GLUT3, are expressed in placental tissues and are responsible for glucose transfer from maternal to the fetus. Deficiency in glucose levels may cause detrimental effects on fetal growth and development. It was reported that phenobarbital can be related to occurrence of intrauterine growth retardation (IUGR). Although phenobarbital is known to be an indirect activator of CAR, an orphan nuclear receptor, the interaction between phenobarbital and placental glucose transporters is far from clear. To investigate the impacts of phenobarbital on the expression and functions of placental GLUT1 and GLUT3, compounds including Phenobarbital (an indirect CAR activator), CITCO (a direct CAR activator) and AICAR (an AMPK activator) were used to treat BeWo cells, a cell line derived from human choriocarcinoma and has therefore been used as an in vitro placenta model. In the RT-PCR study, the results showed that, at a concentration of 0.1 mM, phenobarbital down-regulated m-RNA levels of both syncytin and GLUT1, but not GLUT3. However, at concentrations of 0.5 mM and 1 mM, phenobarbital increased m-RNA levels of GLUT1 but decreased that of GLUT3. The treatment of CITCO caused similar effects comparable to that of phenobarbital at a concentration of 0.1 mM. On the other hand, AICAR showed similar effects comparable to that of phenobarbital at concentrations of 0.5 mM and 1 mM. In the cellular uptake study, the results showed that the Km and Vm values of 3H-2-deoxy-D-glucose in un-treated BeWo cells are 0.55±0.01 mM and 28.37±1.93 nmol/10min-mg/ protein, respectively. There is also with a non-saturable constant k=1.46±0.08mL/10min.mg /protein .After the treatment (24 hours) of 0.5 mM phenobarbital, the Km and Vm values of 3H-2-deoxy-D-glucose are 1.04±0.03 mM and 30.35±1.57 nmol/10min-mg/ protein, respectively. Non-saturable constant k is 0.89±0.04mL/ 10 min.mg /protein. After the treatment (24 hours and 72 hours) of 1 mM phenobarbital, the Km and Vm values of 3H-2-deoxy-D-glucose are 1.05±0.22mM and 34.52±4.49 nmol/10min-mg/ protein (24 hours), 1.08±0.23 mM and 24.49±4.16 nmol/10min.mg/protein (72 hours) respectively. Non-saturable constant k is 1.38±0.13 mL/ 10 min.mg /protein(24 hours) and 0.83±0.07 mL/10min.mg /protein(72 hours). In conclusion, the impacts of phenobarbital on GLUT1 and GLUT3 are concentration-dependent, in which phenobarbital activates CAR at low concentration and AMPK at high concentration, respectively. Given that plasma levels of phenobarbital are about 0.1 mM, this study indicate that phenobarbital may decrease placental glucose transfer by activating CAR. After the treatment of 0.5 mM and 1 mM phenobarbital, Vmax is unchanged but the value of Km increase 24 hours later.After 1 mM phenobarbital treatment, Vmax is decreased than control. These results suggest that the affinity of glucose transporters decrease after phenobarbital treatment. In higher concentration of phenobarbital treatment, the transport ability of glucose transporters is no significantly changed under physiological condition after 24 hours. However, higher concentration of phenobarbital (1 mM) treat 72 hours, the transport ability of glucose transporters is somehow decreased.

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"Expression of divalent metal transporter 1 (DMT-1) in human placenta and fetal tissues of early pregnancy." 2003. http://library.cuhk.edu.hk/record=b5891564.

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Kwan Pui-Chun. Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. Includes bibliographical references (leaves 140-155). Abstracts in English and Chinese. Chapter Chapter 1 --- Introduction Chapter 1.1 --- Overview --- p.1 Chapter 1.2 --- Iron homeostasis --- p.5 Chapter 1.3 --- Natural Resistance Associated Marcophage Protein (Nramp) Family --- p.15 Chapter 1.4 --- Divalent Metal Transporter 1 (DMT1) --- p.18 Chapter 1.5 --- Iron Responsive Element (IRE) and Iron Regulatory Protein (IRP) --- p.23 Chapter 1.6 --- Expression and localization of DMT-1 in human --- p.27 Chapter 1.7 --- Iron and the developing feus --- p.31 Chapter 1.8 --- Objectives of the study --- p.36 Chapter Chapter 2 --- Materials and Method Chapter 2.1 --- Study population --- p.37 Chapter 2.2 --- Procedure of surgical termination of pregnancy --- p.38 Chapter 2.3 --- Tissues collection and preparation --- p.39 Chapter 2.4 --- Semi-quantitative Reverse Transcription-Polymerase Chain Reaction --- p.44 Chapter 2.5 --- Immunohistochemistry --- p.49 Chapter 2.6 --- Statistical analysis --- p.55 Chapter Chapter 3 --- Results Chapter 3.1 --- Description of subjects --- p.56 Chapter 3.2 --- Existence of human DMT-1 isoforms at early pregnancy --- p.58 Chapter 3.3 --- Relative expression of DMT-1 isoforms to β -actin mRNA expression at different week gestation --- p.67 Chapter 3.4 --- Cellular localization of DMT-1 isoforms at early pregnancy --- p.91 Chapter 3.5 --- Relative expression of DMT-1 proteins at early pregnancy --- p.101 Chapter Chapter 4 --- Discussion Chapter 4.1 --- Existence of DMT-1 at early pregnancy --- p.116 Chapter 4.2 --- Expression of DMT-1 isoforms at early pregnancy at gene level --- p.118 Chapter 4.3 --- Expression of DMT-1 isoforms at early pregnancy at protein level --- p.120 Chapter 4.4 --- "Comparison expression of DMT-1 between human fetus, human adult and animal studies" --- p.121 Chapter 4.5 --- Functional importance of DMT-1 at developing fetus at early pregnancy --- p.130 Chapter 4.6 --- Conclusion --- p.138 Chapter 4.7 --- Further study --- p.139 Chapter Chapter 5 --- Reference --- p.140 Appendix I: Calculation of EM --- p.156

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Shearman, Lauren Patricia. "Cocaine-sensitive monoamine transporters in rat placenta labeled with (iodine-125)RTI-55 and tritiated nisoxetine." 1996. https://scholarworks.umass.edu/dissertations/AAI9619437.

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Some of the adverse effects of prenatal cocaine exposure have been associated with uteroplacental vasculature, and (3H) cocaine binding sites were previously reported in human placental villus tissue (Ahmed et al., 1990). Specific uptake systems for serotonin (5-HT) and norepinephrine (NE) are present in human placental syncytiotrophoblastic cells and may be substrates for cocaine action (Cool et al.. 1990; Ramamoorthy et al., 1993b). To investigate whether monoamine transporters are present in rat placenta, I studied the characteristics of placental cocaine recognition sites, and the influence of maternal cocaine treatment on placental and fetal brain monoamine transporter binding. First, saturation analyses were performed with (125I) RTI-55, a potent cocaine congener, on membrane fractions from gestational day (GD) 20 rat placenta. Results yielded curvilinear Scatchard plots that were resolved by non-linear curve-fitting into high- and low-affinity components. Mean Kd values were 0.29 nM and 7.9 nM for high- and low-affinity binding sites respectively, and resembled those found in adult rat brain. Drug displacement studies with monoamine uptake inhibitors indicated that the majority of high-affinity (125I) RTI-55 binding was to the 5-HT transporter. The selective ligands (3H) GBR 12935 and (3H) nisoxetine were used to ascertain whether the rat placenta also possessed dopamine (DA) and/or NE transporters. No saturable binding was detected with (3H) GBR 12935. In contrast, the NE transporter-selective ligand (3H) nisoxetine labeled a single population of binding sites with a Kd of 1.0 nM and a Bmax of 1.2 pmol/mg protein. Drug competition studies confirmed that (3H) nisoxetine labeled NE transporters in rat placenta. Additionally, monoamine transporter binding was localized in GD 20 placenta using in vitro film and dry emulsion autoradiography. (3H) Nisoxetine-labeled NE transporters were visible throughout the placenta, with high densities in giant trophoblastic cells and moderate labeling in the labyrinth. Cocaine-like binding sites labeled with (125I) RTI-55 were mainly distributed in the labyrinth and decidua. To verify the presence of 5-HT transporters in rat placenta, 5-HT immunocytochemistry was carried out. The distribution of 5-HT-immunoreactive cells paralleled sites of (125I) RTI-55 binding in the rat placenta. In the final experiment, pregnant dams received cocaine continuously via s.c. Silastic implants from GD 17 to GD 20, and changes in fetal brain and placental (125I) RTI-55 and (3H) nisoxetine binding were assessed. Cocaine treatment did not alter (125I) RTI-55 binding in the placenta. No effect was found in fetal brain, whereas cocaine produced a marked upregulation of NE transporter density in the placenta at GD 20. These studies demonstrate that rat placenta, a noninnervated tissue, possesses cocaine-like binding sites and 5-HT and NE transporters. Placenta is thus a potential target for mediating some effects of cocaine on fetal development.

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Lamparelli, Rosario D. V. "Ferritin as an iron transport protein ferritin uptake and iron ultilisation by guinea pig placenta." Thesis, 1990. https://hdl.handle.net/10539/24785.

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A dissertation submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg in fulfilment of the Degree of Master of Science in the branch of Medicine The guinea pig clears circulating tissue ferritin in a manner different from other mammals. Previous work in man and in rats has shown that injected tissue ferritin is removed from the plasma predominantly by the liver; however, in the guinea pig it is cleared predominantly by red cell precursors and furthermore, the ferritin iron is utilised directly for haem synthesis. During pregnancy, the foeto-placental complex also has a high requirement for iron. IT2018

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Pollex, Erika. "Fetal Exposure to Antidiabetic Drugs: The Role of the Placenta." Thesis, 2010. http://hdl.handle.net/1807/24857.

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Gestational diabetes, a common medical complication in pregnancy, may lead to severe fetal consequences if left untreated. A major concern with the use of antidiabetic drugs in pregnancy is the potential for placental transfer and fetal toxicity. The presence of endocytic pathways and several ABC transporter proteins has been demonstrated in the human placenta and are believed to play an important role in determining fetal exposure to drugs used in pregnancy. The objective of this thesis is to investigate the safety and transfer of the oral hypoglycemic agent, glyburide, and the new long acting insulin analog, insulin glargine, across the human placenta. The oral antidiabetic, glyburide, has been shown to be actively effluxed across the placenta in the fetal to maternal direction. The transport of glyburide in the presence of a breast cancer resistance protein (BCRP) inhibitor was investigated in the dually perfused human placenta model. The results of the perfusion studies indicate that BCRP plays a role in protecting the fetus from the accumulation of glyburide. Subsequently, cellular studies were carried out to determine the effect of the naturally occurring single nucleotide polymorphism within the coding region of BCRP (C421A/Q141K) on glyburide transport. Results suggest that glyburide transport may be reduced in the presence of the Q141K polymorphism. While insulin remains as the gold standard, the potential for maternal hypoglycemia with insulin injection has resulted in the development of insulin analogs. Insulin glargine, a human insulin analog, has a long half life with no pronounced peak when compared to currently used NPH insulin. Human placental perfusion experiments examining the extent and rate of transfer of insulin glargine across the placenta demonstrated that, at therapeutic concentrations, insulin glargine does not cross the placenta to a measurable extent. To further determine the fetal safety of insulin glargine therapy compared with NPH insulin, a systematic review and meta-analysis were performed. No evidence was identified for increased adverse fetal outcomes with the use of insulin glargine during pregnancy. Overall, the results of this research serve to provide improved treatment options for women with diabetes in pregnancy.

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Marková, Eliška. "Hodnocení vlivu vybraných nových antiretrovirálních léčiv na transport karnitinu v placentě." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-397846.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Eliška Marková Suprevisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Study of the effect of novel antiretroviral drugs on carnitine transport in the placenta Nowadays, the antiretroviral treatment of HIV-positive pregnant women is the standard approach for restriction of transmission of HIV infection from mother to the fetus. In spite of necessity of this pharmacotherapy, it is important to know its safety and risks. For the correct fetal development and function of placenta it is (besides others) essential to ensure the optimal supply of L-carnitine, the key factor for oxidation of fatty acids from mother's blood to the placenta and fetal blood circulation. The deficiency of L-carnitine generally leads to significant metabolic changes in the cells and in it usually demonstrated with cardiomyopathies and myopaties. Published studies indicate higher incidence of cardiovascular diseases and cardiomyopathies in children born to mothers treated with antiretroviral therapy during pregnancy. Optimal transport of carnitine into the placental cells, is ensured due to the presence of functional transport protein OCTN2 in the apical membrane of trophoblast. The aim of this study was...

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Riols, Mathilde. "Étude de l'effet d'un antagoniste se liant au récepteur à la PTHRP (PTH1R) sur les niveaux d'expression d'ARNm de protéines intervenant dans le transport de calcium via le placenta humain." Mémoire, 2008. http://www.archipel.uqam.ca/1358/1/M10444.pdf.

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Durant la grossesse, 30 g de calcium de la mère vers le foetus sont transférés à travers le placenta à raison de 140 mg/Kg/jour pendant le troisième trimestre. Cet apport calcique est primordial au bon développement du foetus notamment dans la formation de ses os et ses dents. De plus, le calcium passant au travers du placenta provient à la fois de la diète maternelle et de la résorption des os maternels afin de subvenir convenablement aux besoins foetaux. Il est donc essentiel que la consommation de calcium par la mère soit suffisante, qu'il y ait une bonne efficacité du transport transplacentaire et que le foetus présente une bonne aptitude à fixer cet ion. Il existe des protéines permettant le transport de calcium comme les canaux TRPV faisant passer le calcium de la circulation maternelle vers le cytoplasme des syncytiotrophoblastes, les CaBPs responsables du transport de calcium dans le cytoplasme, ainsi que la pompe PMCA assurant le transfert du calcium des syncytiotrophoblastes vers la circulation foetale contre le gradient de calcium, aidées potentiellement par l'échangeur Na+/Ca2+. Le but de cette étude est de caractériser la régulation de l'expression de ces protéines responsables du transfert calcique dans le placenta en fonction de la présence ou non de l'action des hormones PTH et PTHrP via le récepteur PTH1R. En effet, ces deux hormones favoriseraient l'expression des protéines à caractère calcium en se liant au récepteur PTH1R. La lignée de cellules de carcinome humain (JEG-3) est traitée ou non avec l'antagoniste aux deux récepteurs PTH (7-34). Les cellules sont traitées pendant 4 jours, et les ARNm sont extraits après 2 et 4 jours de traitement. L'expression des différentes protéines à calcium est quantifiée par PCR en temps réel. On s'attendrait à une diminution de l'expression de celles-ci en absence de signalisation via le récepteur PTH1R puisque PTHrP est un facteur connu pour maintenir le gradient calcique allant de la circulation maternelle à foetale, et que sa concentration dans la circulation augmente fortement au moment où le transport de calcium est à son maximum; et la PTH est également connu pour être un facteur hypercalcémiant. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Placenta, Calcium, Transport, PTH, PTHrP, PTH1R.

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Gravel, Ariane. "Étude du transport de l'acide linoléique dans le placenta humain : influences des profils lipidique et hormonal maternels ainsi que de l'indice de masse corporelle maternel." Mémoire, 2008. http://www.archipel.uqam.ca/1318/1/M10287.pdf.

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La prévalence accrue de surplus pondéral et d'obésité chez les femmes en âge de procréer est un problème de santé publique. De nombreuses études ont démontré qu'un poids maternel trop faible ou trop élevé peut influencer le poids du nouveau-né et ainsi influencer son état de santé actuelle et future. Durant la grossesse, l'accumulation de gras foetal survient au dernier tiers. La disponibilité des acides gras essentiels pour le foetus ne dépend pas seulement de l'apport maternel en acide gras mais aussi de la fonction placentaire elle-même ainsi que des changements et des adaptations physiologiques et biochimiques qui surviennent durant la grossesse. Afin de vérifier l'influence d'un poids maternel hors norme sur ces facteurs de disponibilité des acides gras, l'isolation de cellules trophoblastiques a été effectuée à partir de placenta frais provenant de femmes ayant une masse corporelle au-dessous de la normale (IMC<20 kg/m²), de femmes ayant une masse corporelle normale (20 kg/m²<IMC<26 kg/m²) et de femmes obèses (BMI>30 kg/m²). Ces femmes faisaient partie d'une banque de femmes recrutées pour participer au Projet Lipides de notre laboratoire de physiologie materno-foetale. Des études de transport d'acide linoléique, un acide gras essentiel, ont ensuite été effectuées sur des syncytiotrophoblaste et des cytotrophoblastes isolées à partir des placentas des femmes recrutées pour le projet. Par la suite, ce transport d'acide linoléique a été mis en relation avec les dosages maternelles lipidiques et hormonaux des deuxième et troisième tiers ainsi qu'avec les dosages lipidiques et hormonaux foetaux à la naissance. Cette étude met en évidence une diminution du transport syncytiotrophoblastique de l'acide linoléique par la maigreur et l'obésité pré-grossesse maternelle. En fait, le transport de l'acide linoléique est davantage perturbé dans les syncytiotrophoblastes, que dans les cellules trophoblastiques précurseurs, les cytotrophoblastes. De plus, l'obésité (lMC>30) pré-grossesse a été corrélée à une augmentation des niveaux maternels d'insuline lors du deuxième et troisième tiers ainsi qu'à une diminution des concentrations de TSH et d'AFP. D'autre part, la maigreur (lMC<20) pré-grossesse diminue les niveaux d'AFP et de T3 du troisième tiers et du sang foetal à terme. Ces importantes altérations des niveaux hormonaux qui surviennent durant les grossesses de femmes obèses et de femmes maigres pourraient expliquer la diminution du transport placentaire de l'acide linoléique, un acide gras essentiel. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Grossesse, Placenta, Obésité, Indice de masse corporelle, Trophoblaste.

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Strachoňová, Šárka. "Studium regulace genové exprese nukleosidových transportérů v buněčné linii BeWo." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-397841.

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Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Šárka Strachoňová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Studium of gene regulation of nucleoside transporters in BeWo cell line Nucleoside transporters (NTs) localized in syncytiotrophoblast control placental uptake of nucleosides. Dysregulation of NTs can disrupt nucleoside homeostasis with a negative consequences on placental and fetal development and can lead to a change in placental pharmacokinetics of nucleoside-derived drugs. Therefore, understanding the expression and function of NTs is necessary for effective and safe pharmacotherapy during pregnancy. The aim of this diploma thesis was to study the adenylate cyclase (AC) activated regulatory pathways of gene expression of concentrative nukleoside transporter 2 (CNT2). For this purpose, qRT-PCR and in vitro accumulation assays using the model substrate [3 H]-adenosine were employed. The human placental choriocarcinoma-derived BeWo cell line has been exposed to an AC activator, forskolin (50 µM), and/or inhibitors of AC/cAMP/PKA, AC/cAMP/MAPK (MEK1/2, p38 MAPK) signaling pathways, PKA inhibitor, KT 5720 (5 μM), an inhibitor of MEK1/2, U0126 (10 μM) and an inhibitor of p38 MAPK, SB202190 (10 μM). The...

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Poudrier, Isabelle. "Effet du peptide apparenté à la parathormone sur la différenciation et le transport calcique des trophoblastes humains." Mémoire, 2010. http://www.archipel.uqam.ca/2914/1/M11358.pdf.

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Lors de la grossesse, différentes complications peuvent survenir et amener des conséquences néfastes sur la santé de la mère et du foetus. Par exemple, une malformation du placenta peut mener à des conditions pathologiques telles le retard de croissance intra-utérin ou la pré-éclampsie. Ces maladies semblent, respectivement, être causées par un désordre lors de la différenciation des cytotrophoblastes en syncytiotrophoblastes et une altération du transport de calcium de la mère au foetus. Il est donc essentiel de découvrir les mécanismes cellulaires et moléculaires qui régissent ces phénomènes afin de pouvoir, dans l'avenir, contrer le développement de telles conditions pathologiques. Chez la souris, le transport placentaire du calcium est dépendant du peptide apparenté à la parathormone (PTHrP) et son fragment N-terminal est impliqué dans le processus de différenciation des trophoblastes. Ainsi, cette étude a pour but premier de découvrir si la PTHrP (1-34) régule le transport calcique à travers les syncytiotrophoblastes humains. Par ailleurs, comme les Mitogen Activated Protein Kinases (MAPK) ERK1/2 et p38 sont impliquées dans le processus de différenciation des trophoblastes humains, cette étude vise aussi à déterminer si la PTHrP (1-34) peut stimuler la différenciation des trophoblastes humains via ces deux MAPKs. Il a tout d'abord été nécessaire de mettre au point un milieu de culture sans sérum pour observer les effets directs de l'hormone sur la différenciation cellulaire. Les cellules trophoblastiques sont isolées à partir de placentas humains frais et cultivées dans un milieu de culture sans sérum où la PTHrP est ajoutée en concentrations croissantes. Tout d'abord, la cytotoxicité cellulaire des différents traitements a été mesurée. La différenciation des cellules trophoblastiques est ensuite mesurée de manière biochimique par le dosage de l'hormone hCG et, de manière morphologique, par l'observation de la fusion cellulaire. L'activation des voies de signalisation de ERK1/2 et p38 est observée par irnmunobuvardage de type Western et par la capacité de l'hormone de réactiver la voie de signalisation suite à son blocage par un inhibiteur spécifique. La captation du calcium par les syncytiotrophoblastes est étudiée à l'aide de calcium radiomarqué (⁴⁵Ca²⁺) alors que l'effet de la PTHrP (1-34) sur les protéines impliquées dans le transport de l'ion calcique est étudié par PCR en temps réel et par immunobuvardage de type Western. Les résultats obtenus indiquent que les différents traitements administrés aux cellules trophoblastiques ne causent pas de mortalité cellulaire. Par la suite, nous avons constaté qu'une forte concentration de l'hormone stimule la différenciation des cellules cytotrophoblastiques en syncytiotrophoblastes. Ce processus de différenciation semble se faire par la MAPK ERK1/2 puisque cette dernière est davantage activée en présence de PTHrP (1-34). De plus, le fragment N-terminal de la PTHrP est capable de réactiver cette MAPK suite à son inhibition. Par la suite, il a été possible de constater que la présence du fragment N-terminal de la PTHrP dans le milieu de culture des cellules trophoblastiques permet une augmentation significative de l'expression des protéines PMCA1 et 4 au premier jour de culture. Ainsi, une perturbation de la concentration de PTHrP (1-34) pourrait être un phénomène impliqué dans des conditions pathologiques lors de la grossesse chez la femme enceinte. Éventuellement, il serait donc intéressant d'observer l'effet de cette hormone sur la différenciation et le transport calcique des trophoblastes chez des femmes atteintes de pré-éclampsie ou dont l'enfant souffre de retard de croissance intra-utérin. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Placenta, Trophoblaste, PTHrP, Différenciation, ERK1/2, p38, Calcium.

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Amyot, Marc. "Étude de l'influence d'un KO en PTHRP ou en PTH1R sur le niveau d'expression des protéines de manutention du calcium dans le placenta de souris." Mémoire, 2008. http://www.archipel.uqam.ca/1474/1/M10603.pdf.

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Le peptide apparenté à la parathormone (PTHrP) est un régulateur important du transport de calcium placentaire durant la gestation. Une concentration adéquate de calcium est requise afin d'assurer la croissance et le bon développement du foetus. Dans la présente étude, l'impact d'une délétion en PTHrP ou en son récepteur (PTH1R) a été mesuré dans le placenta de souris. L'usage d'un tel modèle animal a permis d'évaluer l'importance de la PTHrP dans le transport de calcium placentaire mais également les répercussions de telles délétions sur l'expression d'ARNm des protéines de manutention du calcium («calcium handling proteins») présentes dans le placenta (TRPVs, CaBPs, PMCAs, NCXs, TCTP et VDR). Les mesures de calcium ionisé récoltées dans le sang foetal et maternel ont été effectuées in situ en utilisant un analyseur à électrolytes et de sang total. L'évaluation des niveaux d'expression d'ARNm des différentes protéines de manutention du calcium a été rendue possible grâce à la technique de PCR en temps réel. Les résultats obtenus ont démontré que la perte en PTHrP ou en PTH1R engendre une réduction significative du calcium ionisé dans la circulation foetale. Le niveau de calcium ionisé mesuré, chez les foetus ayant subi une délétion en PTHrP ou en PTH1R, est inférieur à celui de la souche sauvage mais équivalent à celui des mères. Dans les placentas de souris délétées en PTHrP, l'expression des gènes de TRPV6 et de TCTP est augmentée contrairement à celle des placentas de la souche sauvage. La délétion du récepteur PTH1R a eu une influence remarquable sur l'expression des médiateurs de calcium CaBP-9k et TCTP mais également sur le récepteur à la vitamine D (VDR). Toujours en comparaison avec les placentas de la souche sauvage, le TCTP et le VDR se sont vus réprimés dans les placentas délétés en PTH1R. L'expression du TRPV5, responsable de l'intrusion du calcium dans le placenta, a également été réduite. D'un autre côté, l'expression d'ARNm de la CaBP-9k a doublé par rapport au niveau d'expression basal lors d'une dysfonction du récepteur. Ces données démontrent donc que la TRPV6 et le TCTP sont les principales protéines de manutention du calcium réagissant à une délétion de la PTHrP. Dans les placentas délétés en PTH1R, aucune variation dans l'expression des ARNm des canaux responsables de l'expulsion du calcium vers la circulation foetale (les PMCA et les NCX) a été remarquée. Pour ce qui est de l'expression de l'ARNm des TRPV, responsables de l'entrée de calcium vers le placenta, elle s'est vue diminuer pour TRPV5 mais inchangée pour TRPV6. Encore une fois, dans ces placentas, l'expression des médiateurs de calcium intracellulaire a été réduite pour le TCTP, inchangée pour la CaBP-28k mais augmentée dans le cas de la CaBP-9k. En conclusion, le transport de calcium placentaire est sans aucun doute réduit lors d'une délétion en PTHrP ou en PTH1R. L'expression des ARNm des protéines de manutention du calcium présentes dans le placenta varie suite à la perte de la PTHrP ou du récepteur PTH1R. Étonnamment, aucune modification significative n'a été constatée dans l'expression des ARNm des protéines responsables de l'extrusion du calcium. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Placenta, Calcium, PTHrP, PTH1R, «Calcium handling proteins».

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