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Heinz Nau - One of the best experts on this subject based on the ideXlab platform.

  • comparative teratology and transplacental pharmacokinetics of all trans retinoic Acid 13 cis retinoic Acid and retinyl palmitate following daily administrations in rats
    Toxicology and Applied Pharmacology, 1994
    Co-Authors: Michael D Collins, Georg Tzimas, Hans Hummler, H Burgin, Heinz Nau
    Abstract:

    Abstract The retinoids are teratogenic in a wide variety of species. In the rat, 13- cis -retinoic Acid and retinyl palmitate are significantly less potent teratogens than all- trans -retinoic Acid. This investigation questioned whether differing teratogenic potencies of these moieties can be correlated with the concentrations of these drugs and/or metabolites in the embryonic compartment. Approximately equipotent teratogenic doses of these three retinoids were administered and the pharmacokinetics in maternal plasma and embryo of the most prevalent vitamin A metabolites were measured. The glucuronides of the respective retinoids were the predominant metabolites in the maternal plasma, but were not detected in the embryo. Also, the transport of 13- cis -retinoic Acid across the placenta occurred to a much lesser extent than the transport of all- trans -retinoic Acid. Administration of either all- trans - or 13- cis -retinoic Acid causes a depression in the endogenous retinol concentration. This depression is more pronounced in the maternal plasma than in the embryo. The depression of the retinol level in both plasma and embryo after 13- cis -retinoic Acid administration (75 mg/kg/day) was greater than the depression after all- trans -retinoic Acid (6 mg/kg/day), corroborating the inferential teratological data that the 13- cis -retinoic Acid dose was more embryotoxic than the all- trans -retinoic Acid dose. Although the dose of all- trans -retinoic Acid was less embryotoxic than that of either 13- cis -retinoic Acid or retinyl palmitate, the embryonic exposure to all- trans -retinoic Acid was considerably larger, as determined by maximum concentration or area under the concentration-versus-time curve, after administration of all- trans -retinoic Acid than after either retinyl palmitate or 13- cis -retinoic Acid application. These results suggest that embryonic retinoids other than all- trans -retinoic Acid-including the administered substances themselves-are important in the teratogenic process induced by 13- cis -retinoic Acid and retinyl palmitate.

Wu Gang - One of the best experts on this subject based on the ideXlab platform.

  • Heterodimeric BMP-2/7 Antagonizes the Inhibition of All-Trans Retinoic Acid and Promotes the Osteoblastogenesis
    plos one, 2013
    Co-Authors: Bi Wenjuan, Gu Zhiyuan, Zheng Yuanna, Zhang Xiao, Guo Jing, Wu Gang
    Abstract:

    Objectives: Hypervitaminosis A and alcoholism can result in a low mineral density and compromised regenerative capacity of bone, thus delaying implant osteointegration. The inhibitory effect of all-trans retinoic Acid on osteoblastogenesis is considered to be one of the mechanisms. We hypothesized that heterodimeric bone morphogenetic protein-2/7 could antagonize all-trans retinoic Acid and enhance osteoblastogenesis, with an aim to accelerate and enhance bone regeneration and implant osteointegration. Materials and Methods: We applied 5 ng/ml or 50 ng/ml bone morphogenetic protein-2/7 to restore the osteoblastogenesis of pre-osteoblasts (MC3T3-E1 cell line) that was inhibited by 1 mu M all-trans retinoic Acid. We evaluated the efficacy by assessing cell numbers (proliferation), alkaline phosphatase activity (a marker for early differentiation), osteocalcin (a marker for late differentiation), calcium deposition (a marker for final mineralization) and the expression of osteoblastogenic genes (such as Runx2, Collagen Ia, alkaline phosphatase and osteocalcin) at different time points. Results: All-trans retinoic Acid significantly inhibited the expression of all the tested osteoblastogenic genes and proteins except alkaline phosphatase activity. In the presence of ATRA, 50 ng/ml bone morphogenetic protein-2/7 not only completely restored but also significantly enhanced all the osteoblastogenic genes and proteins. On the 28th day, mineralization was completely inhibited by all-trans retinoic Acid. In contrast, 50 ng/ml BMP-2/7 could antagonize ATRA and significantly enhance the mineralization about 2.5 folds in comparison with the control treatment (no ATRA, no BMP2/7). Conclusions: Heterodimeric bone morphogenetic protein-2/7 bears a promising application potential to significantly promote bone regeneration and implant osteointegration for the patients with hypervitaminosis A and alcoholism.Multidisciplinary SciencesSCI(E)1ARTICLE10null

  • Heterodimeric BMP-2/7 Antagonizes the Inhibition of All-Trans Retinoic Acid and Promotes the Osteoblastogenesis
    Public Library of Science, 2013
    Co-Authors: Bi Wenjuan, Gu Zhiyuan, Zheng Yuanna, Zhang Xiao, Guo Jing, Wu Gang
    Abstract:

    Hypervitaminosis A and alcoholism can result in a low mineral density and compromised regenerative capacity of bone, thus delaying implant osteointegration. The inhibitory effect of all-trans retinoic Acid on osteoblastogenesis is considered to be one of the mechanisms. We hypothesized that heterodimeric bone morphogenetic protein-2/7 could antagonize all-trans retinoic Acid and enhance osteoblastogenesis, with an aim to accelerate and enhance bone regeneration and implant osteointegration.We applied 5 ng/ml or 50 ng/ml bone morphogenetic protein-2/7 to restore the osteoblastogenesis of pre-osteoblasts (MC3T3-E1 cell line) that was inhibited by 1 µM all-trans retinoic Acid. We evaluated the efficacy by assessing cell numbers (proliferation), alkaline phosphatase activity (a marker for early differentiation), osteocalcin (a marker for late differentiation), calcium deposition (a marker for final mineralization) and the expression of osteoblastogenic genes (such as Runx2, Collagen Ia, alkaline phosphatase and osteocalcin) at different time points. day, mineralization was completely inhibited by all-trans retinoic Acid. In contrast, 50 ng/ml BMP-2/7 could antagonize ATRA and significantly enhance the mineralization about 2.5 folds in comparison with the control treatment (no ATRA, no BMP2/7).Heterodimeric bone morphogenetic protein-2/7 bears a promising application potential to significantly promote bone regeneration and implant osteointegration for the patients with hypervitaminosis A and alcoholism

Hans F Merk - One of the best experts on this subject based on the ideXlab platform.

  • 13 cis retinoic Acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all trans retinoic Acid and binding to retinoid Acid receptors
    Journal of Investigative Dermatology, 2000
    Co-Authors: Miki Tsukada, Mandy Schroder, Constantin E Orfanos, Christos C Zouboulis, Thomas C Roos, Roshantha A S Chandraratna, Uwe Reichert, Hans F Merk
    Abstract:

    Despite its potent biologic effect on human sebocytes, 13- cis retinoic Acid exhibits low binding affinity for cellular retinoic Acid binding proteins and nuclear retinoid receptors. Hence, 13- cis retinoic Acid may represent a pro-drug possibly acting through all- trans isomerization. In this study, marked isomerization of 13- cis retinoic Acid has been confirmed in cultured SZ95 sebocytes showing 2- to 15-fold higher levels of all- trans retinoic Acid at 12–72 h, as measured by high performance liquid chromatography. In contrast, only low amounts of all- trans retinoic Acid were converted intracellularly to its 13- cis isoform. 9- cis retinoic Acid was not detected after either 13- cis retinoic Acid or all- trans retinoic Acid treatment. The rapid isomerization of 13- cis retinoic Acid to high levels of all- trans retinoic Acid was a sebocyte-specific event, as no significant isomerization of 13- cis retinoic Acid to all- trans retinoic Acid occurred in HaCaT keratinocytes. De novo mRNA expression of cytochrome P450 1A1, a major xenobiotic metabolizing enzyme, in SZ95 sebocytes was induced by all- trans retinoic Acid, but not by 13- cis retinoic Acid. In addition, mRNA levels of cellular retinoic Acid-binding protein II, which is supposed to regulate the concentration of intracellular all- trans retinoic Acid, rapidly increased under all- trans retinoic Acid treatment (30 min-6 h), whereas the 13- cis retinoic Acid effect was markedly weaker and delayed. Both 13- cis retinoic Acid and all- trans retinoic Acid suppressed mRNA expression of cytochrome P450 1A2. In parallel experiments, 13- cis retinoic Acid significantly reduced SZ95 sebocyte proliferation at 10 -7 M, showing 30–40% inhibition after 9 d. All- trans retinoic Acid and 9- cis retinoic Acid exhibited similar anti-proliferative effects. AGN 193109, a pan-antagonist of the retinoic Acid receptors, antagonized the anti-proliferative activity of all retinoic Acid isomers tested in a concentration-dependent manner with complete abolishment at ratios of 1:10 13- cis retinoic Acid and 1:1 all- trans retinoic Acid. Coincubation of SZ95 sebocytes with 13- cis retinoic Acid and AGN 193109 did not alter the intracellular concentration of 13- cis retinoic Acid and its isomerization profile. In contrast, the retinoid X receptor antagonist CD 3507 did not affect the inhibition of SZ95 sebocyte proliferation induced by retinoic Acids. Our findings indicate: (i) a selective 13- cis retinoic Acid isomerization to all- trans retinoic Acid in the intracellular compartment of SZ95 sebocytes; (ii) a reduced all- trans retinoic Acid inactivation process after 13- cis retinoic Acid treatment as compared with treatment with all- trans retinoic Acid; and (iii) a retinoic Acid receptor-mediated inhibition of SZ95 sebocyte proliferation. These data explain the sebocyte-specific activity of 13- cis retinoic Acid and support a pro-drug/drug relation between 13- cis retinoic Acid and all- trans retinoic Acid.

Michael D Collins - One of the best experts on this subject based on the ideXlab platform.

  • comparative teratology and transplacental pharmacokinetics of all trans retinoic Acid 13 cis retinoic Acid and retinyl palmitate following daily administrations in rats
    Toxicology and Applied Pharmacology, 1994
    Co-Authors: Michael D Collins, Georg Tzimas, Hans Hummler, H Burgin, Heinz Nau
    Abstract:

    Abstract The retinoids are teratogenic in a wide variety of species. In the rat, 13- cis -retinoic Acid and retinyl palmitate are significantly less potent teratogens than all- trans -retinoic Acid. This investigation questioned whether differing teratogenic potencies of these moieties can be correlated with the concentrations of these drugs and/or metabolites in the embryonic compartment. Approximately equipotent teratogenic doses of these three retinoids were administered and the pharmacokinetics in maternal plasma and embryo of the most prevalent vitamin A metabolites were measured. The glucuronides of the respective retinoids were the predominant metabolites in the maternal plasma, but were not detected in the embryo. Also, the transport of 13- cis -retinoic Acid across the placenta occurred to a much lesser extent than the transport of all- trans -retinoic Acid. Administration of either all- trans - or 13- cis -retinoic Acid causes a depression in the endogenous retinol concentration. This depression is more pronounced in the maternal plasma than in the embryo. The depression of the retinol level in both plasma and embryo after 13- cis -retinoic Acid administration (75 mg/kg/day) was greater than the depression after all- trans -retinoic Acid (6 mg/kg/day), corroborating the inferential teratological data that the 13- cis -retinoic Acid dose was more embryotoxic than the all- trans -retinoic Acid dose. Although the dose of all- trans -retinoic Acid was less embryotoxic than that of either 13- cis -retinoic Acid or retinyl palmitate, the embryonic exposure to all- trans -retinoic Acid was considerably larger, as determined by maximum concentration or area under the concentration-versus-time curve, after administration of all- trans -retinoic Acid than after either retinyl palmitate or 13- cis -retinoic Acid application. These results suggest that embryonic retinoids other than all- trans -retinoic Acid-including the administered substances themselves-are important in the teratogenic process induced by 13- cis -retinoic Acid and retinyl palmitate.

Bi Wenjuan - One of the best experts on this subject based on the ideXlab platform.

  • Heterodimeric BMP-2/7 Antagonizes the Inhibition of All-Trans Retinoic Acid and Promotes the Osteoblastogenesis
    plos one, 2013
    Co-Authors: Bi Wenjuan, Gu Zhiyuan, Zheng Yuanna, Zhang Xiao, Guo Jing, Wu Gang
    Abstract:

    Objectives: Hypervitaminosis A and alcoholism can result in a low mineral density and compromised regenerative capacity of bone, thus delaying implant osteointegration. The inhibitory effect of all-trans retinoic Acid on osteoblastogenesis is considered to be one of the mechanisms. We hypothesized that heterodimeric bone morphogenetic protein-2/7 could antagonize all-trans retinoic Acid and enhance osteoblastogenesis, with an aim to accelerate and enhance bone regeneration and implant osteointegration. Materials and Methods: We applied 5 ng/ml or 50 ng/ml bone morphogenetic protein-2/7 to restore the osteoblastogenesis of pre-osteoblasts (MC3T3-E1 cell line) that was inhibited by 1 mu M all-trans retinoic Acid. We evaluated the efficacy by assessing cell numbers (proliferation), alkaline phosphatase activity (a marker for early differentiation), osteocalcin (a marker for late differentiation), calcium deposition (a marker for final mineralization) and the expression of osteoblastogenic genes (such as Runx2, Collagen Ia, alkaline phosphatase and osteocalcin) at different time points. Results: All-trans retinoic Acid significantly inhibited the expression of all the tested osteoblastogenic genes and proteins except alkaline phosphatase activity. In the presence of ATRA, 50 ng/ml bone morphogenetic protein-2/7 not only completely restored but also significantly enhanced all the osteoblastogenic genes and proteins. On the 28th day, mineralization was completely inhibited by all-trans retinoic Acid. In contrast, 50 ng/ml BMP-2/7 could antagonize ATRA and significantly enhance the mineralization about 2.5 folds in comparison with the control treatment (no ATRA, no BMP2/7). Conclusions: Heterodimeric bone morphogenetic protein-2/7 bears a promising application potential to significantly promote bone regeneration and implant osteointegration for the patients with hypervitaminosis A and alcoholism.Multidisciplinary SciencesSCI(E)1ARTICLE10null

  • Heterodimeric BMP-2/7 Antagonizes the Inhibition of All-Trans Retinoic Acid and Promotes the Osteoblastogenesis
    Public Library of Science, 2013
    Co-Authors: Bi Wenjuan, Gu Zhiyuan, Zheng Yuanna, Zhang Xiao, Guo Jing, Wu Gang
    Abstract:

    Hypervitaminosis A and alcoholism can result in a low mineral density and compromised regenerative capacity of bone, thus delaying implant osteointegration. The inhibitory effect of all-trans retinoic Acid on osteoblastogenesis is considered to be one of the mechanisms. We hypothesized that heterodimeric bone morphogenetic protein-2/7 could antagonize all-trans retinoic Acid and enhance osteoblastogenesis, with an aim to accelerate and enhance bone regeneration and implant osteointegration.We applied 5 ng/ml or 50 ng/ml bone morphogenetic protein-2/7 to restore the osteoblastogenesis of pre-osteoblasts (MC3T3-E1 cell line) that was inhibited by 1 µM all-trans retinoic Acid. We evaluated the efficacy by assessing cell numbers (proliferation), alkaline phosphatase activity (a marker for early differentiation), osteocalcin (a marker for late differentiation), calcium deposition (a marker for final mineralization) and the expression of osteoblastogenic genes (such as Runx2, Collagen Ia, alkaline phosphatase and osteocalcin) at different time points. day, mineralization was completely inhibited by all-trans retinoic Acid. In contrast, 50 ng/ml BMP-2/7 could antagonize ATRA and significantly enhance the mineralization about 2.5 folds in comparison with the control treatment (no ATRA, no BMP2/7).Heterodimeric bone morphogenetic protein-2/7 bears a promising application potential to significantly promote bone regeneration and implant osteointegration for the patients with hypervitaminosis A and alcoholism