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Chemical Society Reviews Aug 2011Small molecules that perturb developmental signaling pathways can have devastating effects on embryonic patterning, as evidenced by the chemically induced onset of... (Review)
Review
Small molecules that perturb developmental signaling pathways can have devastating effects on embryonic patterning, as evidenced by the chemically induced onset of cyclopic lambs and children with severely shortened limbs during the 1950s. Recent studies, however, have revealed critical roles for these pathways in human disorders and diseases, spurring the re-examination of these compounds as new targeted therapies. In this tutorial review, we describe four case studies of teratogenic compounds, including inhibitors of the Hedgehog (Hh), Wnt, and bone morphogenetic protein (BMP) pathways. We discuss how these teratogens were discovered, their mechanisms of action, their utility as molecular probes, and their potential as therapeutic agents. We also consider current challenges in the field and possible directions for future research.
Topics: Animals; Body Patterning; Bone Morphogenetic Proteins; Growth and Development; Hedgehog Proteins; Heterocyclic Compounds, 3-Ring; Humans; Pyrazoles; Pyrimidines; Signal Transduction; Small Molecule Libraries; Teratogens; Thalidomide; Veratrum Alkaloids; Wnt Proteins
PubMed: 21505654
DOI: 10.1039/c1cs15019g -
Computational and Mathematical Methods... 2022and record that Radix Veratri root is and the root of . According to () , Radix Veratri is a Liliaceae plant Veratrum taliense. Another literature pointed out that...
BACKGROUND
and record that Radix Veratri root is and the root of . According to () , Radix Veratri is a Liliaceae plant Veratrum taliense. Another literature pointed out that the aliases of Veratrum taliense and Veratrum angustifolia are both Radix Veratri, and their effects are basically the same. The main active ingredient of Veratrum is veratramine, of which veratramine and Jervine are higher in content, reaching 24.60% and 21.28% of the total alkaloids, respectively. Veratrum alkaloids are both toxic and effective ingredients. In addition to its good clinical efficacy, attention should also be paid to its pharmacokinetic characteristics in vivo. It is particularly important to study the pharmacokinetic characteristics of veratramine and Jervine in vivo.
OBJECTIVE
The goal of this study was to develop a simple and effective method for measuring veratramine and Jervine in rat plasma at the same time. This method was used to study the pharmacokinetic characteristics of veratramine and Jervine in the alcohol extract of Radix Veratri in rats, to provide a reasonable basis for the clinical use of Radix Veratri.
METHODS
Eighteen SD rats were randomly assigned into three groups, half male and half female, and were given 0.04 g/kg, 0.08g/kg, and 0.16 g/kg Radix Veratri alcohol extract, respectively. Blood samples were collected at different time points and were analyzed by LC-MS/MS after protein precipitation. Bullatine was set as the internal standard; the plasma samples were extracted with ethyl acetate. After the sample was processed, acetonitrile-10 mM ammonium acetate, whose pH was adjusted to 8.8 with ammonia water, was taken as the mobile phase. Veratramine quantitative ion pair was 410.1⟶295.1/, Jervine quantitative ion pair was 426.2⟶114.1/, and Bullatine B (IS) quantitative ion pair was 438.2⟶420.1/. In the positive ion mode, the multireaction monitoring (MRM) mode was used to determine the blood concentration of veratramine and Jervine. DAS 3.3.0 was used to calculate the relevant pharmacokinetic parameters.
RESULTS
Veratramine had a good linear relationship in the concentration range of 0.0745~18.2 ng/mL, and that of Jervine was 1.11~108 ng/mL. The correlation coefficient of three consecutive batches of the standard curve was greater than 0.995. Veratramine's lower quantification limit was 0.745 ng/mL, Jervine's was 1.11 ng/mL, and precision and accuracy were both less than 15%. The accuracy of veratramine was between 88.96% and 101.85%, and the accuracy of Jervine was between 92.96% and 104.50%. This method was adopted for the pharmacokinetic study of alcohol extracts of Radix Veratri. The results showed that only of veratramine female rats did not show linear kinetic characteristics in the dose range of Radix Veratri alcohol extract from 0.04 g/kg to 0.16 g/kg. For AUC and of veratramine and Jervine, it could not determine whether the Radix Veratri alcohol extract showed linear kinetic characteristics within the dosage range of 0.04 g/kg~0.16 g/kg. Veratramine and Jervine showed obvious gender differences in the absorption and elimination stages. The absorption rate of veratramine and Jervine by male mice was about 10 times higher than that of female mice, and the elimination rate of male mice is about 20 times lower than that of female mice. It was suggested that the clinical application of the steroidal alkaloids veratramine and Jervine in Radix Veratri required rational use of drugs based on gender.
CONCLUSION
An LC-MS/MS analysis method suitable for the pharmacokinetic study of veratramine and Jervine in Radix Veratri in SD rats was established to provide a basis for in vivo pharmacokinetic studies. The pharmacokinetic characteristics of veratramine and Jervine in the alcohol extract of Radix Veratri were significantly different in female and male rats. During the clinical use of Radix Veratri, it should pay close attention to the obvious gender differences that may occur after the medication.
Topics: Alkaloids; Animals; Chromatography, Liquid; Female; Humans; Male; Mice; Plant Extracts; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Veratrum; Veratrum Alkaloids
PubMed: 35785141
DOI: 10.1155/2022/8289548 -
Cellular and Molecular Life Sciences :... Nov 2000Holoprosencephaly, or an undivided forebrain, is a complex brain malformation associated with Sonic hedgehog (Shh) mutations. Other causes of holoprosencephaly have... (Review)
Review
Holoprosencephaly, or an undivided forebrain, is a complex brain malformation associated with Sonic hedgehog (Shh) mutations. Other causes of holoprosencephaly have converged upon the Shh signaling pathway: genetic and pharmacologic impairment of cholesterol synthesis, and the action of the steroidal alkaloid cyclopamine. This review focuses on recent studies aimed at determining how Shh signaling is affected by these causes of holoprosencephaly, whether they involve a common mechanism and the role played by cholesterol. Cholesterol is potentially important for both biogenesis of Shh and in signal transduction in Shh-responsive cells. Teratogens that induce holoprosencephaly appear to affect Shh signal transduction rather than Shh biogenesis. Analysis of these agents and other compounds that affect various aspects of cellular cholesterol distribution indicates that the role of cholesterol in Shh signal transduction is novel and complicated. The similarity of the Shh receptor, Patched (Ptc), to the Niemann-Pick Cl protein, which is involved in the vesicular trafficking of cholesterol, provides insight into the role of cholesterol and the action of compounds like cyclopamine.
Topics: Animals; Biological Transport, Active; Carrier Proteins; Cholesterol; Hedgehog Proteins; Holoprosencephaly; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Membrane Proteins; Models, Biological; Mutation; Niemann-Pick C1 Protein; Patched Receptors; Proteins; Receptors, Cell Surface; Signal Transduction; Teratogens; Trans-Activators; Veratrum Alkaloids; trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride
PubMed: 11130177
DOI: 10.1007/PL00000653 -
Quarterly Bulletin. Northwestern... 1954
Topics: Female; Pre-Eclampsia; Pregnancy; Veratrum Alkaloids
PubMed: 13215750
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Apr 2023Cyclopamine (1), the teratogenic steroidal alkaloid isolated from corn lily (Veratrum californicum), has recently gained renewed interest due to its anticancer...
Cyclopamine (1), the teratogenic steroidal alkaloid isolated from corn lily (Veratrum californicum), has recently gained renewed interest due to its anticancer potential, that has been translated into the FDA approval of three Hedgehog (Hh) pathway inhibiting antitumor drugs. A chemical analysis of mother liquors obtained from crystallization of cyclopamine, extracted from roots and rhizomes of V. californicum, resulted in the isolation of two unprecedented cyclopamine analogues, 18-hydroxycyclopamine (2) and 24R-hydroxycyclopamine (3), the first compounds of this class to show modifications on rings D-F. The stereostructures of these new natural compounds have been established based on a detailed MS and 1D/2D NMR investigation. The isolated compounds were evaluated with the dual-luciferase bioassay for their inhibition of the hedgehog pathway in comparison to cyclopamine, providing new insights into the structure-activity relationships for this class of compounds.
Topics: Veratrum; Hedgehog Proteins; Veratrum Alkaloids; Alkaloids
PubMed: 37001245
DOI: 10.1016/j.bmc.2023.117265 -
The Journal of General Physiology Nov 1960The interactions of veratridine, cevadine, veracevine, and veratramine with monolayers of stearic acid show marked differences. Veratridine and cevadine, at...
The interactions of veratridine, cevadine, veracevine, and veratramine with monolayers of stearic acid show marked differences. Veratridine and cevadine, at concentrations that are known from potential, ionic flux, and other measurements to affect living membranes, react strongly with the film and appear to cause an "interfacial dissolution" whereby both the alkaloid and the stearate leave the surface. Veracevine at the same concentration does not interact with the film. The veratramine reaction is weak, much like that of the local anesthetic procaine. The veratridine and cevadine effects are antagonized by 10(-3)M Ca(++), low pH, and 3.7 and 7.4 x 10(-3)M procaine. These differences among the veratrum alkaloids and the antagonisms parallel effects observed in living systems. Such parallelism suggests that similar physical interactions are involved in the stearate film and in natural membranes.
Topics: Anesthetics, Local; Calcium; Procaine; Stearates; Stearic Acids; Veratrine; Veratrum; Veratrum Alkaloids
PubMed: 13750673
DOI: 10.1085/jgp.44.2.345 -
Nature Communications Jun 2021The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD) subtypes and Smoothened (SMO), remains one of the most enigmatic GPCR...
The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD) subtypes and Smoothened (SMO), remains one of the most enigmatic GPCR families. While SMO relies on cholesterol binding to the 7TM core of the receptor to activate downstream signaling, underlying details of receptor activation remain obscure for FZDs. Here, we aimed to investigate the activation mechanisms of class F receptors utilizing a computational biology approach and mutational analysis of receptor function in combination with ligand binding and downstream signaling assays in living cells. Our results indicate that FZDs differ substantially from SMO in receptor activation-associated conformational changes. SMO manifests a preference for a straight TM6 in both ligand binding and functional readouts. Similar to the majority of GPCRs, FZDs present with a kinked TM6 upon activation owing to the presence of residue P. Functional comparison of FZD and FZD PF mutants in different assay formats monitoring ligand binding, G protein activation, DVL2 recruitment and TOPflash activity, however, underlines further the functional diversity among FZDs and not only between FZDs and SMO.
Topics: Binding Sites; Bioluminescence Resonance Energy Transfer Techniques; Boron Compounds; Cryoelectron Microscopy; Cyclic AMP-Dependent Protein Kinases; Frizzled Receptors; Humans; Molecular Dynamics Simulation; Mutation; Phosphoproteins; Protein Conformation; Smoothened Receptor; Veratrum Alkaloids
PubMed: 34168128
DOI: 10.1038/s41467-021-24004-z -
Fitoterapia Sep 2019Veratrum californicum is a rich source of steroidal alkaloids, many of which have proven to be antagonists of the Hedgehog (Hh) signaling pathway that becomes aberrant...
Veratrum californicum is a rich source of steroidal alkaloids, many of which have proven to be antagonists of the Hedgehog (Hh) signaling pathway that becomes aberrant in over twenty types of cancer. These alkaloids first became known in the 1950's due to their teratogenic properties, which resulted in newborn and fetal lambs developing cyclopia as a result of pregnant ewes consuming Veratrum californicum. It was discovered that the alkaloids in V. californicum were concentrated in the root and rhizome of the plant with much lower amounts of the most active alkaloid, cyclopamine, present in the aerial plant, especially in the late growth season. Inspired by the limitations in analytical instrumentation and methods available to researchers at the time of the original investigation, we have used state-of-the-art instrumentation and modern analytical methods to quantitate four steroidal alkaloids based on study parameters including plant part, harvest location, and growth stage. The results of the current inquiry detail differences in alkaloid composition based on the study parameters, provide a detailed assessment for alkaloids that have been characterized previously (cyclopamine, veratramine, muldamine and isorubijervine), and identify at least six alkaloids that have not been previously characterized. This study provides insight into optimal harvest time, plant growth stage, harvest location, and plant part required to isolate, yet to be characterized, alkaloids of interest for exploration as Hh pathway antagonists with desirable medicinal properties.
Topics: Alkaloids; Hedgehog Proteins; Idaho; Molecular Structure; Phytochemicals; Plant Components, Aerial; Rhizome; Seasons; Steroids; Veratrum; Veratrum Alkaloids
PubMed: 31381957
DOI: 10.1016/j.fitote.2019.104281 -
Kidney International Jul 1981
Review
Topics: Aldosterone; Animals; Anura; Canrenoic Acid; Canrenone; Cattle; Guinea Pigs; Humans; Male; Mineralocorticoid Receptor Antagonists; Rats; Receptors, Steroid; Spironolactone; Veratrum Alkaloids
PubMed: 7029118
DOI: 10.1038/ki.1981.97 -
The Turkish Journal of Gastroenterology... Mar 2020To investigate the effect and the possible mechanism of lanthanum citrate on the proliferation and apoptosis of human hepatocellular carcinoma (HCC) cell line SMMC-7721...
BACKGROUND/AIMS
To investigate the effect and the possible mechanism of lanthanum citrate on the proliferation and apoptosis of human hepatocellular carcinoma (HCC) cell line SMMC-7721 through the Hedgehog (Hh) signaling pathway.
MATERIALS AND METHODS
Different concentrations of lanthanum citrate and KAAD-cyclopamine (the Hh signaling pathway representative inhibitor) were used to treat SMMC-7721 cells. Cell proliferation was detected using Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays. Cell apoptosis was detected using flow cytometry analysis of Annexin V-FITC/ propidium iodide (PI). The protein expressions of regulatory genes, such as cell cycle protein D1 (CyclinD1), cyclin-dependent kinase inhibitor 1 (p21), cysteinyl aspartate specific proteinase 3 (Caspase-3), B-cell lymphoma-2 (Bcl-2), glioma-associated oncogene homolog 1 (Gli1), and sonic hedgehog (Shh) were quantified using Western blot assays. The mRNA expressions of Gli1 and Shh were tested using quantitative real-time polymerase chain reaction (qRT-PCR) assays and the protein expressions of Gli1 and Shh were determined using immunofluorescence assays.
RESULTS
The Annexin V-FITC and PI double staining results revealed that the 0.1 mM lanthanum citrate group and the 15 µM KAAD-cyclopamine group had both increased the apoptosis rate of SMMC-7721 cells. Both lanthanum citrate and KAAD-cyclopamine downregulated the protein expressions of CyclinD1, Bcl-2, Gli1, and Shh and upregulated the protein expressions of p21 and Caspase-3. Additionally, the immunofluorescence results revealed that the protein expressions of Gli1 and Shh were significantly decreased in both the lanthanum citrate group and the KAAD-cyclopamine group compared to the control group.
CONCLUSION
Lanthanum citrate inhibits proliferation and promotes apoptosis in HCC SMMC-7721 cells by suppressing the Hh signaling pathway.
Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cinnamates; Citrates; Hedgehog Proteins; Humans; Liver Neoplasms; Signal Transduction; Veratrum Alkaloids
PubMed: 32343239
DOI: 10.5152/tjg.2020.18800