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1.

001-es BibID:BIBFORM036665
Első szerző:Elmazar, Mohamed M. A.
Cím:RARalpha-Mediated Teratogenicity in Mice Is Potentiated by an RXR Agonist and Reduced by an RAR Antagonist : dissection of Retinoid Receptor-Induced Pathways / Elmazar M. M., Rühl R., Reichert U., Shroot B., Nau H.
Dátum:1997
ISSN:0041-008X
Megjegyzések:To dissect the complex pattern of retinoid-induced developmental defects, an RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative) was coadministered with an RARalpha-selective agonist (Am580, an arylcarboxamidobenzoic acid derivative) to NMRI mice on Day 8.25 of gestation. AGN191701 was neither fetotoxic nor teratogenic at the doses used, but potentiated Am580-induced resorptions, spina bifida aperta, micrognathia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, tail malformations, fused ribs, and fetal weight retardation. These effects were generally reduced by coadministration of an RAR-selective antagonist (CD2366, an adamantyl-methoxyphenyl-heptatrienoic acid derivative). The incidence of other defects induced by an RARalpha-selective agonist such as exencephaly or cleft palate was neither greatly affected by the RXR-selective agonist nor by the antagonist. These results suggest that some malformations such as the posterior neural tube defect spina bifida as well as urogenital defects may be mediated via liganded RARalpha-RXR heterodimerization, while other defects such as the anterior neural tube defect exencephaly as well as cleft palate are induced by different mechanisms.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Toxicology And Applied Pharmacology. - 146 : 1 (1997), p. 21-28. -
További szerzők:Rühl, Ralph (1969-) (vegyész) Reichert, Uwe Shroot, B. Nau, Heinz
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2.

001-es BibID:BIBFORM036662
Első szerző:Elmazar, Mohamed M. A.
Cím:Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalpha- or RARgamma-selective agonist with a RXR-selective agonist / Elmazar M. M., Rühl R., Nau H.
Dátum:2001
ISSN:0041-008X
Megjegyzések:To study the interaction of retinoid-induced limb defects and cleft palate on day 11 of gestation, a RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative, 20 mg/kg orally) was coadministered with a RARalpha-agonist (Am580, an arylcarboxamidobenzoic acid derivative, 5 mg/kg orally) to NMRI mice. AGN191701 was neither fetotoxic nor teratogenic at the dose used but potentiated Am580-induced limb defects and cleft palate and prevented Am580-induced fetal weight retardation. These results suggest that Am580-induced limb defects and probably cleft palate on day 11 of gestation may be mediated via RARalpha-RXR heterodimerization, particularly in the absence of toxicokinetic interactions. AGN191701 was also coadministered with a RARgamma-agonist (CD437, an adamantyl-hydroxyphenyl naphthoic acid derivative, 15 mg/kg orally) on days 8 and 11 of gestation to investigate which CD437-induced defects are mediated via RARgamma-RXR heterodimerization. On day 8 of gestation, AGN191701 potentiated CD437-induced embryolethality, exencephaly, spina bifida aperta, cleft palate, and tail defects, as well as visceral and skeletal defects, but not micrognathia. On day 11 of gestation, the incidence of CD437-induced cleft palate and limb defects was also potentiated when coadministered with the RXR agonist. These results suggest that synergistic teratogenic effects can be induced by coadministration of two receptor-selective retinoids, indicating the importance of RARalpha-RXR and RARgamma-RXR heterodimers in producing structural defects during organogenesis.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Toxicology And Applied Pharmacology. - 170 : 1 (2001), p. 2-9. -
További szerzők:Rühl, Ralph (1969-) (vegyész) Nau, Heinz
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3.

001-es BibID:BIBFORM036667
Első szerző:Foerster, M.
Cím:Comparative studies on effects of all-trans-retinoic acid and all-trans-retinoyl-beta-d-glucuronide on the development of foetal mouse thymus in an organ culture system / Foerster, M., Sass, J. O., Rühl, R., Nau, H.
Dátum:1996
ISSN:0887-2333
Megjegyzések:The thymus is a target organ of retinoid teratogens. Retinoids with a generally reduced teratogenic potency should therefore also exert reduced adverse effects on thymus development. The effects of all-trans-retinoic acid (a-tRA) and all-trans-retinoyl-beta-glucuronide (a-tRAG) on the in vitro development of thymic lobes of 15-day-old mouse foetuses were compared in an organ culture system. Both compounds were added to the medium at concentrations ranging from 10(-7) to 10(-5)m. The culture period was 6 days. The investigations showed a concentration-dependent effect of both substances on the proliferation of the lymphatic cells. At 10(-5)m the number of thymocytes was significantly reduced to values of about 70% of the controls by either of the retinoids (P 0.05). Results of flow cytometry showed significant differences concerning the differentiation markers CD4 and CD8 after the culture period. The presence of 10(-6)m a-tRA induced a significant increase in the percentages of CD4(+)CD8(-) cells and a significant decrease of CD4(+)CD8(+) cells. At 10(-5)m a-tRA an additional significant increase in the percentages of CD4(-)CD8(-) cells was found. In contrast, after treatment with a-tRAG, percentages of these populations were in the same range as the controls. Light and electron microscopic investigations revealed a depletion of lymphatic cells and an increase of intracytoplasmic vacuoles in the thymic epithelial cells at 10(-6) and 10(-5)m of either retinoid. HPLC analyses revealed a remarkable degree of retinoid isomerization and (in the case of a-tRAG) of hydrolysis. Compared with the culture medium, retinoids were accumulated in the thymic lobes. Possibly a-tRAG acts by way of limited hydrolysis to retinoic acid.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Toxicology In Vitro. - 10 : 1 (1996), p. 7-15. -
További szerzők:Sass, Jörn Rühl, Ralph (1969-) (vegyész) Nau, Heinz
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4.

001-es BibID:BIBFORM036648
Első szerző:Fritzsche, Britta
Cím:CYP26A1-specific antagonist influence on embryonic implantation, gene expression and endogenous retinoid concentration in rats / Fritzsche Britta, Schuchardt Jan-Philipp, Schmidt Anja, Nau Heinz, Schweigert Florian J., Rühl Ralph
Dátum:2010
ISSN:0890-6238
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:Reproductive Toxicology. - 30 : 3 (2010), p. 446-451. -
További szerzők:Schuchardt, Jan-Philipp Schmidt, Anja Nau, Heinz Schweigert, Florian J. Rühl, Ralph (1969-) (vegyész)
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5.

001-es BibID:BIBFORM036663
Első szerző:Krätke, Renate
Cím:All- trans -retinoic acid and all- trans -retinoyl-beta-d -glucuronide alter the development of axolotl embryos ( Ambystoma mexicanum ) in vitro / Renate Krätke, Ralph Rühl, Frank Kirschbaum, Heinz Nau
Dátum:2000
ISSN:0340-5761
Megjegyzések:Retinoids are involved in several physiological processes and are used in the treatment of various skin disorders. Therapy with retinoids during pregnancy may induce severe embryotoxic effects like craniofacial and cardiovascular malformations in the developing embryo. We investigated the effects of all-trans-retinoic acid (ATRA) and all-trans-retinoyl-β-D-glucuronide (ATRAG) in an amphibian embryotoxicity assay with Ambystoma mexicanum (axolotl) as an alternative in vitro method. Embryos were exposed to various concentrations of ATRA or ATRAG for 48 h beginning with the blastula stage. Kinetic investigations in the embryonic tissue were performed during the exposure period. Both retinoids interfered with the development of the axolotl embryos. Dose-dependent effects observed included growth retardation, craniofacial and cardiovascular malformations, as well as neural tube defects. In the axolotl, ATRA induced slightly more pronounced embryotoxic effects than ATRAG. All-trans-retinal was shown to be a major endogenous retinoid in this species. Endogenous levels of all-trans-retinaldehyde were increased during exposure to both ATRA and ATRAG. The glucuronide, however, was only detected in small amounts after ATRAG exposure. The embryotoxic potential of ATRAG could be explained by deglucuronidation to ATRA.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Archives Of Toxicology. - 74 : 3 (2000), p. 173-180. -
További szerzők:Rühl, Ralph (1969-) (vegyész) Kirschbaum, Frank Nau, Heinz
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6.

001-es BibID:BIBFORM037319
Első szerző:Nau, Heinz
Cím:All-trans-retinoyl-beta-glucuronide is a potent teratogen in the mouse because of extensive metabolism to all-trans-retinoic acid / Nau, H., Elmazar, M. M. A., Rühl, R., Thiel, R., Sass, J.
Dátum:1996
Megjegyzések:All-trans-retinoyl-beta-D-glucuronide (all-trans-RAG) is a water-soluble derivative of all-trans-retinoic acid (all-trans-RA) and has been characterized as an endogenous metabolite of vitamin A in rat bile and kidney. All-trans-RAG was previously demonstrated to be a major metabolite after application of all-trans-RA in several species (mouse, rat, rabbit, monkey); all-trans-RAG was described in these experiments to exhibit a very low placental transfer to the embryo. Because retinoid-like activity has been found after application of all-trans-RAG in vivo as well as in several in vitro systems, and because of its low placental transfer, this glycoconjugate appeared to be an interesting retinoid with possible therapeutic activity, but reduced teratogenicity. Here we investigated the teratogenic activity of all-trans-RAG in comparison to all-trans-RA in mice, and performed accompanying pharmacokinetic studies. Surprisingly, all-trans-RAG was more teratogenic than equimolar doses of all-trans-RA following subcutaneous application on day 11 of gestation in the mouse (20 mumol/kg body weight). Pharmacokinetic studies revealed that all-trans-RAG was extensively hydrolyzed to all-trans-RA and that the plasma area under the concentration-time curve (AUC) of all-trans-RA following all-trans-RAG application exceeded the plasma AUC value of all-trans-RA following application of all-trans-RA. Extensive hydrolysis of all-trans-RAG was also observed after intravenous application of this glycoconjugate. Transfer of all-trans-RAG to the embryo was low, but transfer was high to maternal organs such as the liver and kidney. These in vivo studies suggest that all-trans-RAG serves as a precursor of all-trans-RA by the intravenous and subcutaneous routes, and application of all-trans-RAG results in high and teratogenic in vivo exposure to all-trans-RA.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Teratology. - 54 : 3 (1996), p. 150-156. -
További szerzők:Elmazar, Mohamed M. A. Rühl, Ralph (1969-) (vegyész) Thiel, Renate Sass, Jörn
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7.

001-es BibID:BIBFORM036688
Első szerző:Rühl, Ralph (vegyész)
Cím:Determination of adapalene (CD271/differin®) and retinol in plasma and tissue by on-line solid-phase extraction and HPLC analysis / Rühl, R., Nau, H.
Dátum:1997
ISSN:0009-5893
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Chromatographia. - 45 : 1 (1997), p. 269-274. -
További szerzők:Nau, Heinz
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8.

001-es BibID:BIBFORM036661
Első szerző:Rühl, Ralph (vegyész)
Cím:Synthesis, high-performance liquid chromatography-nuclear magnetic resonance characterization and pharmacokinetics in mice of CD271 glucuronide / Rühl Ralph, Thiel Renate, Lacker Tanja Silke, Strohschein Sabine, Albert Klaus, Nau Heinz
Dátum:2001
ISSN:0378-4347
Megjegyzések:Retinoic acid-glucuronides are known as retinoids with activity in acne therapy, limited placental transfer and reduced retinoid adverse effects. We synthesized the glucuronide of a novel retinoid, CD271 (adapalene), used for the treatment of moderate acne. The synthesis product ("CD271 glucuronide", CD271G) was purified by preparative HPLC. It undergoes in aqueous solution, like other glucuronides, rapid acyl-migration of the bound aglycone leading to position isomers. Thus characterization of purified CD271G could be only achieved by HPLC-NMR coupling. A subfraction ("CD271GB") consisting essentially of 2'- and 3'-CD271G was used for pharmacokinetic studies. After a single subcutaneous injection at a dosage of 30 mg/kg the substance showed considerable uptake and metabolism to CD271 indicating that CD271GB could serve as a prodrug for CD271.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal of Chromatography B: Biomedical Sciences and Applications. - 757 : 1 (2001), p. 101-109. -
További szerzők:Thiel, Renate Lacker, Tanja Silke Strohschein, Sabine Albert, Klaus Nau, Heinz
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9.

001-es BibID:BIBFORM036660
Első szerző:Rühl, Ralph (vegyész)
Cím:Embryonic subcellular distribution of 13-cis- and all-trans-retinoic acid indicates differential cytosolic/nuclear localization / Ralph Rühl, Claudia Plum, Mohamed M. A. Elmazar, Heinz Nau
Dátum:2001
Megjegyzések:Isotretinoin (13-cis-retinoic acid [13CRA], Accutane) is used for the treatment of dermatological diseases. Isotretinoin is, however, teratogenic in animals and humans. The mechanism of action of its teratogenicity is still not clearly identified. It has little or no binding properties to cytosolic retinoid-binding proteins or nuclear retinoid receptors (RAR, RXR). One hypothesis is that the teratogenicity of 2 approximately equipotent teratogenic doses of 13CRA and all-trans-retinoic acids (ATRA) could mainly be correlated to ATRA in the nuclei, where the retinoic acid receptors (RARs) are located. To test this hypothesis, female mice at gestational day 11 were treated with approximately equipotent teratogenic doses of 13-cis-retinoic acid (100 mg/kg orally) or all-trans-retinoic acid (10 mg/kg orally) and sacrificed 1 h and 4 h after administration. Embryos were homogenized and centrifuged into 4 fractions, and the purity of the fractions was tested by quantification of marker constituents for various cell compartments. We analyzed, by RP-HPLC, nuclear, mitochondrial, microsomal, and cytosolic fractions, as well as embryo homogenate and maternal plasma. After treatment with 13-cis-retinoic acid, this substance was mainly located in the nuclear fraction of the embryo (approximately 82%), whereas all-trans-retinoic acid, after ATRA treatment, was mainly located in the cytosolic supernatant (approximately 64%). The binding to cellular retinoid-binding protein (CRABP) may limit the access of ATRA to the nucleus, in contrast to 13CRA, which does not bind to CRABP. The concentration of ATRA in the nuclear fraction was similar after administration of either 13CRA or ATRA. The teratogenic activity of 13-cis-retinoic acid could therefore be explained by its access to the nucleus and its possible conversion to all-trans-retinoic acids, which will interact with the nuclear retinoid receptors.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Toxicological Sciences. - 63 : 1 (2001), p. 82-89. -
További szerzők:Plum, Claudia Elmazar, Mohamed M. A. Nau, Heinz
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10.

001-es BibID:BIBFORM036658
Első szerző:Rühl, Ralph (vegyész)
Cím:Effects of all-trans-retinoic acid and all-trans-retinoyl glucuronide in two in vitro systems of distinct biological complexity / Ruhl Ralph, Sass Jörn, Nau Heinz, Klug Stephan
Dátum:2001
ISSN:0340-5761
Megjegyzések:In vitro systems are widely used to evaluate the embryotoxic potential of retinoids. The effective concentrations of these retinoids, however, are not consistent in the various in vitro systems used in evaluating embryotoxicity. This may be explained by the different level of complexity for each individual system, which may lead to different concentrations of the substances in the target tissues. To verify this hypothesis we have compared two in vitro systems of distinct biological complexity: the rat whole embryo culture system, and the mouse limb bud organ culture system. The lipid soluble, teratogenic retinoid all-trans-retinoic acid (ATRA), and all-trans-retinoyl-beta-D-glucuronide (ATRAG), an endogenous, water-soluble and biologically active retinoid with limited placental transfer, were compared with regard to their embryotoxic potential in vitro. In both in vitro systems, ATRAG showed a lower degree of embryotoxicity than ATRA. In the limb bud organ culture, ATRAG revealed only slightly less toxicity than ATRA, whereas the effective concentrations of the two compounds in the whole embryo culture system differed by almost two orders of magnitude. During incubation with ATRAG, ATRA is generated by hydrolysis and is found in culture media and exposed tissues. The presence of membrane barriers around the developing embryo in the whole embryo culture system possibly prevents the transfer of ATRAG to the embryo and, therefore, its exposure to the active hydrolysis product ATRA. From these results we conclude that analysis of retinoid concentrations in the culture media and in the exposed tissues is essential for the interpretation of results obtained from in vitro toxicity testing.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Archives Of Toxicology. - 75 : 8 (2001), p. 497-504. -
További szerzők:Sass, Jörn Nau, Heinz Klug, Stephan
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11.

001-es BibID:BIBFORM036651
Első szerző:Rühl, Ralph (vegyész)
Cím:Identification of 14-hydroxy-retro-retinol and 4-hydroxy-retinol as endogenous retinoids in rats throughout neonatal development / Rühl Ralph, Hamscher Gerd, Garcia Ada L., Nau Heinz, Schweigert Florian J.
Dátum:2005
ISSN:0024-3205
Megjegyzések:14-Hydroxy-retro-retinol was previously described as an in vivo and in vitro metabolite of retinol. Furthermore, the retinoid 4-hydroxy-retinol was identified as an endogenous occurring retinoid in the amphibian organism and an in vitro metabolite of retinol. We describe in the present study that 14-hydroxy-retro-retinol and 4-hydroxy-retinol are present in normal neonatal rat serum as endogenous occurring retinoids in normal non-vitamin A supplemented mammals (rats). Both retinoids were detected in serum and liver of neonatal rats at days 3 and 11 after birth. The respective concentrations at day 11 after birth were 41.8 +/- 2.8 ng/ml (serum)/ 104 +/- 6 ng/g (liver) for 4-hydroxy-retinol and 23 +/- 4.6 ng/ml (serum)/ 285 +/- 5 ng/g (liver) for 14-hydroxy-retro-retinol. Both retinoids could not be detected in adult rat serum and liver. From our experiments important physiological functions of these retinoids during postnatal development could be postulated.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Life Sciences. - 76 : 14 (2005), p. 1613-1622. -
További szerzők:Hamscher, Gerd Garcia, Ada L. Nau, Heinz Schweigert, Florian J.
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12.

001-es BibID:BIBFORM036666
Első szerző:Sass, Jörn
Cím:Effects of all-trans-retinoyl-beta-d-glucuronide and all-trans-retinoic acid on chondrogenesis and retinoid metabolism in mouse limb bud mesenchymal cells in vitro / Sass, J. O., Zimmermann, Bernd, Rühl, Ralph, Nau, Heinz
Dátum:1997
ISSN:0340-5761
Megjegyzések:Retinoids, derivatives of vitamin A, are essential for many vertebrate functions. Furthermore, several drugs of this class of compounds are valuable in the treatment of certain forms of skin disorders and cancer. However, the therapeutic application of retinoids is limited by their teratogenic potency. The limbs are important sites of retinoid-induced malformations in rodents. Therefore, organoid cultures of limb bud mesenchymal cells have been established for screening of the teratogenic potency of retinoids. We have now applied this system to compare the effects of all-trans-retinoyl-β-d-glucuronide (all-trans-RAG) with those of all-trans-retinoic acid (all-trans-RA) on chondrogenesis, as assessed by the Alcian blue binding assay and by electron microscopic evaluation including quantitative morphometric analysis. First data of retinoid toxicokinetics in the culture media as well as retinoid concentrations in the cultured mesenchymal limb bud cells were established. While all-trans-RA inhibited chondrogenesis at 10-7 M by ca. 50%, tenfold higher concentrations of all-trans-RAG were necessary to obtain the same effect. This difference reflects the ratio of RA isomers which were found in the medium after incubation with either all-trans-RAG or all-trans-RA. A pulse experiment (10-5 M all-trans-RAG or all-trans-RA for the first 2 h of a 6-day incubation period) demonstrated inhibition of chondrogenesis with all-trans-RA, but not with all-trans-RAG. The data indicate that RAG inhibits chondrogenesis upon hydrolysis to RA. Surprisingly, the rather polar RAG isoforms were extensively accumulated in the limb bud mesenchymal cells when compared to the medium. Both all-trans-RAG and all-trans-RA also induced a large increase of retinyl ester concentrations in the chondrocytes compared to vehicle-treated cells. This finding further supports a recent suggestion that RA regulates retinol metabolism via feedback inhibition of retinol oxidation and stimulation of the esterification of retinol.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Archives Of Toxicology. - 71 : 3 (1997), p. 142-150. -
További szerzők:Zimmermann, Bernd Rühl, Ralph (1969-) (vegyész) Nau, Heinz
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