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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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2.

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
Internet cím:Intézményi repozitóriumban (DEA) tárolt változat
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3.

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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4.

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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5.

001-es BibID:BIBFORM036671
Első szerző:Zouboulis, Christos C. (bőrgyógyász)
Cím:Retinoid Signaling by all-trans Retinoic Acid and all-trans Retinoyl-beta-D-Glucuronide Is Attenuated by Simultaneous Exposure of Human Keratinocytes to Retinol / Zouboulis, Christos C., Seltmann, Holger, Sass, Jorn Oliver, Ruhl, Ralph, Plum, Claudia, Hettmannsperger, Uwe, Blume-Peytavi, Ulrike, Nau, Heinz, Orfanos, Constantin E.
Dátum:1999
ISSN:0022-202X
Megjegyzések:Retinol and retinyl esters are converted with time to slowly increasing amounts of all-trans retinoic acid (RA) in cultured human keratinocytes. Exogenous RA has been shown to limit retinol oxidation and to increase retinol esterification. Because significant amounts of retinol are present in biologic systems, we examined whether RA and all-trans-retinoyl-beta-D-glucuronide (RAG) interact with retinol in exhibiting their activities on HaCaT keratinocytes maintained in a retinoid-free culture system. RA was more potent than RAG and retinol in inducing ultrastructural changes attributed to retinoids, inhibiting cell proliferation as well as enhancing keratin 19 expression. In addition, retinoids were able to induce cellular retinoic acid-binding protein II mRNA levels in the cultures, whereas early RA and late RAG activity was detected. The described biologic effects of RA and RAG were diminished by simultaneous cell exposure to retinol. HaCaT cells quickly metabolized retinol to retinyl esters and consequently to low amounts of RA. RA treatment led to an early high peak of cellular RA followed by reduction to trace amounts. Treatment with RAG resulted in constantly high cellular RAG and low RA levels. Under the combined RA and retinol treatment retinyl esters were increased and RA was reduced in HaCaT cells, whereas extracellular RA levels were similar to those obtained by RA alone. On the other hand, the combination of RAG and retinol resulted in higher extracellular RAG, similar cellular RAG, and lower cellular RA levels than those obtained by RAG alone without any change in retinyl esters. This study demonstrates that retinoid signaling by RA and RAG is attenuated by simultaneous exposure of HaCaT keratinocytes in vitro to retinol. The presence of retinol in the medium alters the rate of RA or RAG metabolism and thus cellular RA concentrations. The intensity of retinoid signal is probably dependent on cellular RA levels. The resulting "antagonism" among retinoids is consistent with the presence of an auto-regulatory mechanism in human keratinocytes offering protection against excessive accumulation of cellular RA.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal Of Investigative Dermatology. - 112 : 2 (1999), p. 157-164. -
További szerzők:Seltmann, Holger Sass, Jörn Rühl, Ralph (1969-) (vegyész) Plum, Claudia Hettmannsperger, Uwe Blume-Peytavi, Ulrike Nau, Heinz Orfanos, Constantin E.
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