The Experts below are selected from a list of 21 Experts worldwide ranked by ideXlab platform
Wade Bushman - One of the best experts on this subject based on the ideXlab platform.
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dose and route dependent teratogenicity toxicity and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse
Toxicological Sciences, 2008Co-Authors: Robert J Lipinski, Paul R Hutson, Paul W Hannam, Robert J Nydza, Ida M Washington, Robert W Moore, Gary Girdaukas, Richard E Peterson, Wade BushmanAbstract:The Hedgehog (Hh) signaling pathway is an essential regulator of embryonic development and appears to play important roles in postnatal repair and cancer progression and metastasis. The teratogenic Veratrum Alkaloid cyclopamine is a potent Hh antagonist and is used experimentally both in vitro and in vivo to investigate the role of Hh signaling in diverse biological processes. Here, we set out to establish an administration regimen for cyclopamine-induced teratogenicity in the mouse. The dysmorphogenic concentration of cyclopamine was determined in vitro via mouse whole-embryo culture assays to be 2.0μM. We administered cyclopamine to female C57BL/6J mice at varied doses by oral gavage, ip injection, or osmotic pump infusion and assessed toxicity and pharmacokinetic (PK) models. Bolus administration was limited by toxicity and rapid clearance. In vivo cyclopamine infusion at 160 mg/kg/day yielded a dam serum steady-state concentration of ∼2μM with a corresponding amniotic fluid concentration of approximately 1.5μM. Gross facial defects were induced in 30% of cyclopamine-exposed litters, with affected embryos exhibiting cleft lip and palate. This is the first report describing the PKs and teratogenic potential of cyclopamine in the mouse and demonstrates that transient Hh signaling inhibition induces facial clefting anomalies in the mouse that mimic common human birth defects.
Henk Roelink - One of the best experts on this subject based on the ideXlab platform.
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The teratogenic Veratrum Alkaloid cyclopamine inhibits sonic hedgehog signal transduction
Development (Cambridge England), 1998Co-Authors: John P. Incardona, William Gaffield, Raj P. Kapur, Henk RoelinkAbstract:The steroidal Alkaloid cyclopamine produces cyclopia and holoprosencephaly when administered to gastrulationstage amniote embryos. Cyclopamine-induced malformations in chick embryos are associated with interruption of Sonic hedgehog (Shh)-mediated dorsoventral patterning of the neural tube and somites. Cell types normally induced in the ventral neural tube by Shh are either absent or appear aberrantly at the ventral midline after cyclopamine treatment, while dorsal cell types normally repressed by Shh appear ventrally. Somites in cyclopamine-treated embryos show Pax7 expression throughout, indicating failure of sclerotome induction. Cyclopamine at concentrations of 20-100 nM blocks the response of neural plate explants to recombinant Shh-N in a dose-dependent manner. Similar concentrations have no effect on the post-translational modification of Shh by cholesterol in transfected COS-1 cells. Comparison of the effects of cyclopamine to those of the holoprosencephalyinducing cholesterol synthesis inhibitor AY-9944 shows that cyclopamine does not induce malformations by interfering with cholesterol metabolism. Although AY-9944 does not interrupt Shh signaling in ovo, it blocks the response to Shh-N in explants cultured without an exogenous cholesterol source. As predicted by current models of the regulation of cholesterol metabolism, the response to ShhN in AY-9944-treated explants is restored by providing exogenous cholesterol. However, exogenous cholesterol does not restore Shh signaling in cyclopamine-treated explants. These findings suggest that cyclopamine-induced teratogenesis is due to a more direct antagonism of Shh signal transduction. SUMMARY
Galina V. Ramenskaya - One of the best experts on this subject based on the ideXlab platform.
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Veratrum Alkaloid Determination in Four Cases of Veratrum Aqua Poisonings
Journal of analytical toxicology, 2021Co-Authors: Elizaveta V. Melnik, Maria V Belova, Mikhail M Potskhveriya, Anastasiya Yu Simonova, Igor A Tyurin, Galina V. RamenskayaAbstract:Veratrum poisonings are known to the toxicology literature as multiple Veratrum species grow in different parts of the Northern Hemisphere and are occasionally ingested by mistake. Veratrum toxicity is attributed to the steroidal Alkaloids contained in all parts of the plant. In Russia Veratrum poisonings are more common since there is an over-the-counter Veratrum Lobelianum-based tincture, Veratrum Aqua (VA), that is topically used for treatment of lice infestation. Despite its toxicity, VA is misused in traditional medicine as a remedy for alcohol use disorder. We describe four cases of VA poisoning that occurred in Moscow, Russia. Three main Veratrum Lobelianum Alkaloids (jervine, protoveratrine A and protoveratrine B), were determined in patient plasma and urine samples using liquid chromatography tandem mass-spectrometry (LC-MS/MS). Here we describe a novel validated LC-MS/MS method for jervine and protoveratrine A quantification. Simple and rapid liquid-liquid extraction with methyl tert-butyl ether was utilized for analyte extraction. Chromatographic separation was achieved using Poroshell 120 EC-C18 column, and the total run time was 14 min. The lower limit of quantification was 0.1 ng/mL for jervine and proA in both plasma and urine. Biological samples were obtained upon hospital admission and during treatment, thus enabling to get a better understanding of the Alkaloid elimination profile. Upon admission plasma concentrations of jervine (concentration range: 0.10-5.01 ng/mL) prevailed over protoveratrine A (concentration range: 0-0.67 ng/mL). At this time, protoveratrine A already reached maximum concentrations in urine (concentration range: 0.15-37.70 ng/mL). Maximum concentrations of jervine in urine were observed 24 hours after admission (concentration range: 0.10-9.55 ng/mL). In all cases plasma concentrations of Veratrum Alkaloids correlated with condition severity. Since none of the patients confirmed VA intake, instrumental analysis was the basis for the definitive diagnosis of VA poisoning.
Robert J Lipinski - One of the best experts on this subject based on the ideXlab platform.
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dose and route dependent teratogenicity toxicity and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse
Toxicological Sciences, 2008Co-Authors: Robert J Lipinski, Paul R Hutson, Paul W Hannam, Robert J Nydza, Ida M Washington, Robert W Moore, Gary Girdaukas, Richard E Peterson, Wade BushmanAbstract:The Hedgehog (Hh) signaling pathway is an essential regulator of embryonic development and appears to play important roles in postnatal repair and cancer progression and metastasis. The teratogenic Veratrum Alkaloid cyclopamine is a potent Hh antagonist and is used experimentally both in vitro and in vivo to investigate the role of Hh signaling in diverse biological processes. Here, we set out to establish an administration regimen for cyclopamine-induced teratogenicity in the mouse. The dysmorphogenic concentration of cyclopamine was determined in vitro via mouse whole-embryo culture assays to be 2.0μM. We administered cyclopamine to female C57BL/6J mice at varied doses by oral gavage, ip injection, or osmotic pump infusion and assessed toxicity and pharmacokinetic (PK) models. Bolus administration was limited by toxicity and rapid clearance. In vivo cyclopamine infusion at 160 mg/kg/day yielded a dam serum steady-state concentration of ∼2μM with a corresponding amniotic fluid concentration of approximately 1.5μM. Gross facial defects were induced in 30% of cyclopamine-exposed litters, with affected embryos exhibiting cleft lip and palate. This is the first report describing the PKs and teratogenic potential of cyclopamine in the mouse and demonstrates that transient Hh signaling inhibition induces facial clefting anomalies in the mouse that mimic common human birth defects.
John P. Incardona - One of the best experts on this subject based on the ideXlab platform.
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The teratogenic Veratrum Alkaloid cyclopamine inhibits sonic hedgehog signal transduction
Development (Cambridge England), 1998Co-Authors: John P. Incardona, William Gaffield, Raj P. Kapur, Henk RoelinkAbstract:The steroidal Alkaloid cyclopamine produces cyclopia and holoprosencephaly when administered to gastrulationstage amniote embryos. Cyclopamine-induced malformations in chick embryos are associated with interruption of Sonic hedgehog (Shh)-mediated dorsoventral patterning of the neural tube and somites. Cell types normally induced in the ventral neural tube by Shh are either absent or appear aberrantly at the ventral midline after cyclopamine treatment, while dorsal cell types normally repressed by Shh appear ventrally. Somites in cyclopamine-treated embryos show Pax7 expression throughout, indicating failure of sclerotome induction. Cyclopamine at concentrations of 20-100 nM blocks the response of neural plate explants to recombinant Shh-N in a dose-dependent manner. Similar concentrations have no effect on the post-translational modification of Shh by cholesterol in transfected COS-1 cells. Comparison of the effects of cyclopamine to those of the holoprosencephalyinducing cholesterol synthesis inhibitor AY-9944 shows that cyclopamine does not induce malformations by interfering with cholesterol metabolism. Although AY-9944 does not interrupt Shh signaling in ovo, it blocks the response to Shh-N in explants cultured without an exogenous cholesterol source. As predicted by current models of the regulation of cholesterol metabolism, the response to ShhN in AY-9944-treated explants is restored by providing exogenous cholesterol. However, exogenous cholesterol does not restore Shh signaling in cyclopamine-treated explants. These findings suggest that cyclopamine-induced teratogenesis is due to a more direct antagonism of Shh signal transduction. SUMMARY
