The Experts below are selected from a list of 8037 Experts worldwide ranked by ideXlab platform
Matti Poutanen - One of the best experts on this subject based on the ideXlab platform.
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HSD17B1 expression enhances estrogen signaling stimulated by the low active estrone, evidenced by an estrogen responsive element-driven reporter gene in vivo
Chemico-biological interactions, 2015Co-Authors: Päivi Järvensivu, Niina Saarinen, Pasi Koskimies, Taija Saloniemi-heinonen, Michael Awosanya, Matti PoutanenAbstract:Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) belongs to a family of short-chain-dehydrogenases. The enzyme utilizes NAD(P) and NAD(P)H as cofactors, and catalyzes the reversible reaction between estrone (E1) and estradiol (E2) in vitro. Of these steroids, E1 presents with lower estrogenic activity, but is converted to highly active E2 by HSD17B1. HSD17B1 is expressed especially in tissues with a high E2-producing capacity such as human ovaries and placenta, but also in several peripheral estrogen target tissues in humans, and inhibiting the enzyme activity is, thus, considered a promising approach to treat estrogen-dependent diseases. By analyzing transgenic mice universally expressing human HSD17B1 and carrying estrogen-response element (ERE)-driven luciferase reporter gene (Bi-transgenic ERELuc-HSD17B1TG mice) we showed a markedly higher reporter gene activity in various peripheral tissues of these mice as compared with ERELuc mice, indicating enhanced estrogen response generated by human HSD17B1 expression. An increased response after E1 administration was also evident in the Bi-TG mice, indicated by the increased Uterus Growth response and by the higher ERELuc reporter gene activity in the Uterus. Moreover, a HSD17B1 inhibitor significantly reduced E1-induced increase in the Uterus weight and uterine epithelial proliferation in the Bi-TG mice. Also the E1-induced ERELuc activity in the inhibitor-treated Uterus was reduced by the HSD17B1 inhibitor in immature mice ex vivo, as well as in the liver of adult mice. The data, thus, demonstrate the potential use of the Bi-TG mice as a preclinical in vivo model for screening the efficacy of HSD17B1 inhibitors. As compared with the existing models, the Bi-TG mice present with luciferase activity as an additional, easily quantitative endpoint for the estrogen action.
Jochem Louisse - One of the best experts on this subject based on the ideXlab platform.
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towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data
Archives of Toxicology, 2018Co-Authors: Mengying Zhang, Bennard Van Ravenzwaay, Eric Fabian, Ivonne M C M Rietjens, Jochem LouisseAbstract:Physiologically based kinetic (PBK) modelling-based reverse dosimetry is a promising tool for the prediction of in vivo developmental toxicity using in vitro concentration–response data. In the present study, the potential of this approach to predict the dose-dependent increase of Uterus weight in rats upon exposure to estrogenic chemicals was assessed. In vitro concentration–response data of 17β-estradiol (E2) and bisphenol A (BPA) obtained in the MCF-7/BOS proliferation assay, the U2OS ER-CALUX assay and the yeast estrogen screen (YES) assay, were translated into in vivo dose–response data in rat, using a PBK model with a minimum number of in vitro and in silico determined parameter values. To evaluate the predictions made, benchmark dose (BMD) analysis was performed on the predicted dose–response data and the obtained BMDL10 values were compared with BMDL10 values derived from data on the effects of E2 and BPA in the uterotrophic assay reported in the literature. The results show that predicted dose–response data of E2 and BPA matched with the data from in vivo studies when predictions were made based on YES assay data. The YES assay-based predictions of the BMDL10 values differed 3.9-fold (E2) and 4.7- to 13.4-fold (BPA) from the BMDL10 values obtained from the in vivo data. The present study provides the proof-of-principle that PBK modelling-based reverse dosimetry of YES assay data using a minimum PBK model can predict dose-dependent in vivo Uterus Growth caused by estrogenic chemicals. In future studies, the approach should be extended to include other estrogens.
Päivi Järvensivu - One of the best experts on this subject based on the ideXlab platform.
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HSD17B1 expression enhances estrogen signaling stimulated by the low active estrone, evidenced by an estrogen responsive element-driven reporter gene in vivo
Chemico-biological interactions, 2015Co-Authors: Päivi Järvensivu, Niina Saarinen, Pasi Koskimies, Taija Saloniemi-heinonen, Michael Awosanya, Matti PoutanenAbstract:Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) belongs to a family of short-chain-dehydrogenases. The enzyme utilizes NAD(P) and NAD(P)H as cofactors, and catalyzes the reversible reaction between estrone (E1) and estradiol (E2) in vitro. Of these steroids, E1 presents with lower estrogenic activity, but is converted to highly active E2 by HSD17B1. HSD17B1 is expressed especially in tissues with a high E2-producing capacity such as human ovaries and placenta, but also in several peripheral estrogen target tissues in humans, and inhibiting the enzyme activity is, thus, considered a promising approach to treat estrogen-dependent diseases. By analyzing transgenic mice universally expressing human HSD17B1 and carrying estrogen-response element (ERE)-driven luciferase reporter gene (Bi-transgenic ERELuc-HSD17B1TG mice) we showed a markedly higher reporter gene activity in various peripheral tissues of these mice as compared with ERELuc mice, indicating enhanced estrogen response generated by human HSD17B1 expression. An increased response after E1 administration was also evident in the Bi-TG mice, indicated by the increased Uterus Growth response and by the higher ERELuc reporter gene activity in the Uterus. Moreover, a HSD17B1 inhibitor significantly reduced E1-induced increase in the Uterus weight and uterine epithelial proliferation in the Bi-TG mice. Also the E1-induced ERELuc activity in the inhibitor-treated Uterus was reduced by the HSD17B1 inhibitor in immature mice ex vivo, as well as in the liver of adult mice. The data, thus, demonstrate the potential use of the Bi-TG mice as a preclinical in vivo model for screening the efficacy of HSD17B1 inhibitors. As compared with the existing models, the Bi-TG mice present with luciferase activity as an additional, easily quantitative endpoint for the estrogen action.
Katharina Spanelborowski - One of the best experts on this subject based on the ideXlab platform.
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expression of nerve Growth factor ngf isoforms in the rat Uterus during pregnancy accumulation of precursor prongf
Endocrinology, 2005Co-Authors: Edgar Lobos, Claudia Gebhardt, Annett Kluge, Katharina SpanelborowskiAbstract:The mechanisms that promote the transient degenerative changes in the Uterus innervation during pregnancy remain incompletely understood. Signaling by the nerve Growth factor (NGF)-β is important for maintaining the density of peripheral sympathetic innervation. Here, we analyzed the spatial and temporal expression of NGF isoforms in the rat Uterus using RT-PCR, immunoblot analysis, and immunohistochemistry during pregnancy (d 7, 14, and 21), and postpartum (d 1, 8, and 22). Western blot analysis using antibodies to mature NGF-β and to proNGF domain demonstrated a significant decrease in mature NGF-β at gestational d 14 and 21 (term pregnancy) and 1 d postpartum, which paralleled a remarkable accumulation of the 26–28-, 32-, and 60-kDa proNGF forms. There were diminished ratios of mature NGF-β to proNGF independent of Uterus Growth on the same gestational days. Immunohistochemistry revealed a progressive NGF-β decline throughout pregnancy in the myometrium and a near absence at term pregnancy, which contr...
Mengying Zhang - One of the best experts on this subject based on the ideXlab platform.
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towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data
Archives of Toxicology, 2018Co-Authors: Mengying Zhang, Bennard Van Ravenzwaay, Eric Fabian, Ivonne M C M Rietjens, Jochem LouisseAbstract:Physiologically based kinetic (PBK) modelling-based reverse dosimetry is a promising tool for the prediction of in vivo developmental toxicity using in vitro concentration–response data. In the present study, the potential of this approach to predict the dose-dependent increase of Uterus weight in rats upon exposure to estrogenic chemicals was assessed. In vitro concentration–response data of 17β-estradiol (E2) and bisphenol A (BPA) obtained in the MCF-7/BOS proliferation assay, the U2OS ER-CALUX assay and the yeast estrogen screen (YES) assay, were translated into in vivo dose–response data in rat, using a PBK model with a minimum number of in vitro and in silico determined parameter values. To evaluate the predictions made, benchmark dose (BMD) analysis was performed on the predicted dose–response data and the obtained BMDL10 values were compared with BMDL10 values derived from data on the effects of E2 and BPA in the uterotrophic assay reported in the literature. The results show that predicted dose–response data of E2 and BPA matched with the data from in vivo studies when predictions were made based on YES assay data. The YES assay-based predictions of the BMDL10 values differed 3.9-fold (E2) and 4.7- to 13.4-fold (BPA) from the BMDL10 values obtained from the in vivo data. The present study provides the proof-of-principle that PBK modelling-based reverse dosimetry of YES assay data using a minimum PBK model can predict dose-dependent in vivo Uterus Growth caused by estrogenic chemicals. In future studies, the approach should be extended to include other estrogens.
