| cyclopamine and related steroidal alkaloid teratogens: their occurrence, structural relationship, and biologic effects. | a spontaneous congenital deformity is produced in lambs whose dams consume veratrum californicum on the 14th day of gestation. the deformity is generally expressed as cyclopia, cebocephaly, anophthalmia, or microphthalmia. this teratogenic effect is produced by certain steroidal alkaloid teratogens from the plant - most notably the compound cyclopamine. cyclopamine is a c-nor-d-homo steroid with fused furanopiperidine rings e and f at right angles to the plane of the steroid because of spiro att ... | 1978 | 723484 |
| teratogenic effects of cyclopamine and jervine in rats, mice and hamsters. | golden hamster fetuses were extremely sensitive to the teratogenic action of jervine and cyclopamine, the steroidal alkaloid tetratogens from veratrum californicum. cebocephaly, harelip/cleft palate, exencephaly, and a cranial bled were the common deformities produced by dosing on the seventh day of gestation. sprague-dawley derived albino rats were susceptible to cyclopamine but not to jervine, and at an incidence very much lower than that of hamsters. cebocephaly and microphthalmia were the co ... | 1975 | 1144444 |
| expression of veratrum alkaloid teratogenicity in the mouse. | jervine, a steroidal alkaloid found as a minor constituent in the teratogenic range plant veratrum californicum, has produced similar terata in sheep, rabbit, hamster, and chick, although the sensitivity to the alkaloid varies in the different species. sprague dawley rats and swiss webster mice are relatively insensitive. the aim of this study was to determine the teratogenic potential of jervine in three strains of mice and to ascertain if the response is strain dependent. one strain, swiss n:g ... | 1990 | 2218940 |
| early embryonic death in lambs induced by veratrum californicum. | both field and laboratory observations have suggested the possibility of embryonic death from 14th day ingestion of veratrum californicum by pregnant sheep. an experiment was conducted to tabulate the incidence of embryonic death from 14th day ingestion of high doses of plant material. six of eight ewes so dosed were non-pregnant at term (75%), compared to none in controls, and were, therefore, believed to have experienced embryonic death from the plant ingestion. results suggest that ingestion ... | 1990 | 2318044 |
| the nature of congenital limb defects induced in lambs by maternal ingestion of veratrum californicum. | groups of ewes were gavaged veratrum californicum root-rhizome material over various 3 day periods during early gestation and their late-term fetuses examined. resulting from gavage near day 29 were shortening of fetal metacarpal, metatarsal and tibial bones. fibulae bowed severely when tibiae were shortened. medial bowing of forelimbs at the fetlocks resulted from unequal shortening of fused metacarpi. severe joint articular surface defects and arthrogryposis were present in some of the lambs f ... | 1987 | 3669113 |
| congenital tracheal stenosis in lambs induced by maternal ingestion of veratrum californicum. | seven of nine lambs born to six ewes gavaged with veratum californicum root and rhizome material on days 31, 32 and 33 of gestation died from asphyxia within 5 minutes after birth. five of the seven were autopsied and found to have severe stenosis of the trachea. none of the 12 lambs born to seven control ewes had tracheal stenosis. the defect was characterized by lateral flattening of the trachea throughout its entire length. cartilaginous tracheal rings were reduced in number, nonuniform in si ... | 1985 | 3983862 |
| prolonged gestation in ewes ingesting veratrum californicum: morphological changes and steroid biosynthesis in the endocrine organs of cyclopic lambs. | | 1972 | 4622911 |
| teratogenic compounds of veratrum californicum (durand). xiv. limb deformities produced by cyclopamine. | | 1973 | 4694830 |
| proceedings: effects of alkaloids of veratrum californicum on developing embryos. | | 1973 | 4799673 |
| teratogenic compounds in veratrum californicum (durand) ix. structure-activity relation. | | 1970 | 4986631 |
| teratogenic compounds of veratrum californicum (durand) x. cyclopia in rabbits produced by cyclopamine. | | 1970 | 4986632 |
| congenital deformities in lambs, calves, and goats resulting from maternal ingestion of veratrum californicum: hare lip, cleft palate, ataxia, and hypoplasia of metacarpal and metatarsal bones. | | 1972 | 5065665 |
| nonteratogenicity of veratrum californicum in rabbits. | | 1969 | 5388127 |
| teratogenic compounds of veratrum californicum (durand). xi. gestational chronology and compound specificity in rabbits. | | 1971 | 5554462 |
| teratogenic compounds of veratrum californicum (durand). v. comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources. | | 1968 | 5696817 |
| early embryonic death in ewes given veratrum californicum. | | 1969 | 5813016 |
| chronologic evaluation of teratogenicity in sheep fed veratrum californicum. | | 1965 | 5894206 |
| teratogenic compounds of veratrum californicum (durand). ii. production of ovine fetal cyclopia by fractions and alkaloid preparations. | | 1966 | 5950658 |
| teratogenic compounds of veratrum californicum (durand). 3. malformations of the veratramine-induced type from ingestion of plant or roots. | | 1967 | 6079922 |
| teratological research at the usda-ars poisonous plant research laboratory. | research on teratogenic plants started at the usda-agricultural research service-poisonous plant research laboratory in the mid 1950s when dr. wayne binns, director of the laboratory, was asked to investigate the cause of a cyclopian facial/skeletal birth defect in lambs. dr. lynn f. james joined the staff shortly after. these two people worked as a team wherein most planning was done jointly with binns supervising most of the laboratory work and james the field studies. it was determined that w ... | 1999 | 10091129 |
| cyclopamine-induced holoprosencephaly and associated craniofacial malformations in the golden hamster: anatomic and molecular events. | holoprosencephaly is a complex congenital malformation of the brain and is often associated with a spectrum of facial anomalies ranging from normocephaly or nondiagnostic changes to cleft lip/palate (premaxillary dysgenesis), cebocephaly, ethmocephaly, and cyclopia. the primary insult is thought to occur during gastrulation, when prechordal mesenchyme and overlying anterior neural plate undergo complex developmental interactions. exposure to cyclopamine, a steroid isolated from the desert plant ... | 1998 | 10463269 |
| development of an enzyme-linked immunosorbent assay for the veratrum plant teratogens: cyclopamine and jervine. | veratrum californicum was responsible for large losses of sheep grazing high mountain ranges in central idaho in the 1950s. veratrum induces various birth defects including the cyclopic-type craniofacial defect (monkey-faced lambs) that is specifically induced in lambs after pregnant ewes grazed the plant on the 14th day of gestation. the steroidal alkaloids cyclopamine (1) and jervine (2) were isolated from veratrum and shown to be primarily responsible for the malformations. cyclopamine (1) an ... | 2003 | 12537426 |
| a congenital cyclopian-type malformation in lambs induced by maternal ingestion of a range plant, veratrum californicum. | | 1963 | 14081451 |
| toxicosis of veratrum californicum in ewes and its relationship to a congenital deformity in lambs. | | 1964 | 14172731 |
| chemical compounds of veratrum californicum related to congenital ovine cyclopian malformations: extraction of active material. | | 1964 | 14200082 |
| biomedical applications of poisonous plant research. | research designed to isolate and identify the bioactive compounds responsible for the toxicity of plants to livestock that graze them has been extremely successful. the knowledge gained has been used to design management techniques to prevent economic losses, predict potential outbreaks of poisoning, and treat affected animals. the availability of these compounds in pure form has now provided scientists with tools to develop animal models for human diseases, study modes of action at the molecula ... | 2004 | 15161174 |
| in vivo inhibition of endogenous brain tumors through systemic interference of hedgehog signaling in mice. | the full spectrum of developmental potential includes normal as well as abnormal and disease states. we therefore subscribe to the idea that tumors derive from the operation of paradevelopmental programs that yield consistent and recognizable morphologies. work in frogs and mice shows that hedgehog (hh)-gli signaling controls stem cell lineages and that its deregulation leads to tumor formation. moreover, human tumor cells require sustained hh-gli signaling for proliferation as cyclopamine, an a ... | 2005 | 15652709 |
| cyclopamine treatment of full-blown hh/ptch-associated rms partially inhibits hh/ptch signaling, but not tumor growth. | mutations in the hedgehog (hh) receptor patched (ptch) are responsible for a variety of tumors, which show ligand-independent stimulation of the hh/ptch signaling cascade. cyclopamine is an alkaloid of the corn lily veratrum californicum, which blocks activity of the pathway by inhibition of smoothened (smo), the signal transduction partner of ptch. this results in growth inhibition of hh/ptch-dependent tumor cells in vitro, of subcutaneous xenografts as well as of precancerous lesions in ptch(+ ... | 2008 | 17963245 |
| isolation, purification, and full nmr assignments of cyclopamine from veratrum californicum. | the hedgehog signaling pathway is essential for embryogenesis and for tissue homeostasis in the adult. however, it may induce malignancies in a number of tissues when constitutively activated, and it may also have a role in other forms of normal and maladaptive growth. cyclopamine, a naturally occurring steroidal alkaloid, specifically inhibits the hedgehog pathway by binding directly to smoothened, an important hedgehog response element. to use cyclopamine as a tool to explore and/or inhibit th ... | 2008 | 18577213 |
| cyclopamine-induced synophthalmia in sheep: defining a critical window and toxicokinetic evaluation. | cyclopamine, a steroidal alkaloid, from the plant veratrum californicum is teratogenic, causing a range of different birth defects. the critical window for cyclopamine-induced synophthalmia formation has been reported to be gestational day (gd) 14. the objectives of this study were to better describe cyclopamine-induced craniofacial deformities, to better define the window of susceptibility to synophthalmia formation, and to characterize cyclopamine toxicokinetics in sheep. ewes were dosed i.v. ... | 2009 | 19301244 |
| cyclopamine bioactivity by extraction method from veratrum californicum. | veratrum californicum, commonly referred to as corn lily or californian false hellebore, grows in high mountain meadows and produces the steroidal alkaloid cyclopamine, a potent inhibitor of the hedgehog (hh) signaling pathway. the hh pathway is a crucial regulator of many fundamental processes during vertebrate embryonic development. however, constitutive activation of the hh pathway contributes to the progression of various cancers. in the present study, a direct correlation was made between t ... | 2016 | 27338657 |
| micropropagation, acclimatization, and greenhouse culture of veratrum californicum. | micropropagation and production of veratrum californicum is most successful when using a premixed murishage and skoog basal medium with vitamins and a 5-week subculture cycle at 16 °c for multiplication. these culture conditions provide the best percent survival after acclimatization in the greenhouse. however, clone response to temperature and light quality within culture conditions varies. micropropagated plants have mass and morphology similar to 2- or 3-year-old seedlings. acclimatized plant ... | 2016 | 27108318 |
| i only have eye for ewe: the discovery of cyclopamine and development of hedgehog pathway-targeting drugs. | covering: 1950s to 2015during the 1950s, sheep ranchers in the western united states experienced episodic outbreaks of cyclopic lambs. in this highlight i describe how these mysterious incidents were traced to the grazing of veratrum californicum wildflowers by pregnant ewes, leading to the discovery of cyclopamine () as a plant-derived teratogen. the precise mechanism of cyclopamine action remained enigmatic for 30 years, until this steroid alkaloid was found to be the first specific inhibitor ... | 2016 | 26787175 |
| elucidating steroid alkaloid biosynthesis in veratrum californicum: production of verazine in sf9 cells. | steroid alkaloids have been shown to elicit a wide range of pharmacological effects that include anticancer and antifungal activities. understanding the biosynthesis of these molecules is essential to bioengineering for sustainable production. herein, we investigate the biosynthetic pathway to cyclopamine, a steroid alkaloid that shows promising antineoplastic activities. supply of cyclopamine is limited, as the current source is solely derived from wild collection of the plant veratrum californ ... | 2015 | 25939370 |
| cyclopamine: from cyclops lambs to cancer treatment. | in the late 1960s, the steroidal alkaloid cyclopamine was isolated from the plant veratrum californicum and identified as the teratogen responsible for craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in the western united states. cyclopamine was found to inhibit the hedgehog (hh) signaling pathway, which plays a critical role in embryonic development. more recently, aberrant hh signaling has been implicated in several types of cancer. thus, inhib ... | 2014 | 24754790 |
| improved extraction and complete mass spectral characterization of steroidal alkaloids from veratrum californicum. | four steroidal alkaloids extracted from the roots and rhizomes of veratrum californicum were separated by high performance liquid chromatography (hplc) and identified using high resolution electrospray ionization time of flight tandem mass spectrometry (esi-tof-ms/ms) as veratrosine, cycloposine, veratramine, and cyclopamine. this paper compares ethanol and benzene as extraction solvents, hplc solvent conditions leading to good separation of steroidal alkaloids, and ms/ms fragmentation patterns ... | 2013 | 24079166 |
| inhibition of hedgehog/gli signaling by botanicals: a review of compounds with potential hedgehog pathway inhibitory activities. | the hedgehog (hh) signaling pathway is an important therapeutic target in cancer; involvement of the hh pathway has been shown in a variety of cancers including basal cell carcinoma, medulloblastoma, leukemia, and gastrointestinal, breast, prostate, lung, and pancreatic cancers [1-10]. currently, several hh pathway inhibitory drugs are in clinical development, and the fda recently approved erivedge (vismodegib) from curis/genentech [11-15]. these new drugs are effective in many, but not all pati ... | 2013 | 23675897 |
| development of a monoclonal antibody-based elisa for the hedgehog inhibitors cyclopamine and kaad-cyclopamine. | cyclopamine (1) was isolated from the plant veratrum californicum durand (liliacea) and identified as the teratogen responsible for severe craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in central idaho. more recently, cyclopamine (1) was found to inhibit the hedgehog (hh) signaling pathway which plays a critical role in embryonic development and is implicated in several types of cancer. thus, cyclopamine (1) and cyclopamine derivatives have bee ... | 2012 | 22516681 |
| from teratogens to potential therapeutics: natural inhibitors of the hedgehog signaling network come of age. | steroidal alkaloids from veratrum californicum (durand) are known to exert teratogenic effects (e.g., cyclopia, holoprosencephaly) by blocking the hedgehog (hh) signaling pathway, which plays a considerable role in embryonic development and organogenesis. most surprisingly, recent studies demonstrate that this complex signaling network is active even in the healthy adult organism, where it seems to control important aspects of basic metabolism and interorgan homeostasis. abnormal activation of h ... | 2009 | 19639534 |
| phytochemicals: the good, the bad and the ugly? | phytochemicals are constitutive metabolites that enable plants to overcome temporary or continuous threats integral to their environment, while also controlling essential functions of growth and reproduction. all of these roles are generally advantageous to the producing organisms but the inherent biological activity of such constituents often causes dramatic adverse consequences in other organisms that may be exposed to them. nevertheless, such effects may be the essential indicator of desirabl ... | 2007 | 17950388 |
| development of in vitro techniques for the important medicinal plant veratrum californicum. | veratrum californicum (liliaceae) is an important monocotyledonous medicinal plant which is the only source of the anticancer compound cyclopamine. an in vitro culture system for somatic embryogenesis and green plant regeneration of veratrum californicum was developed. embryogenic calli were induced from mature embryos on induction medium. five basal media supplemented with different growth regulators were evaluated for embryogenic callus induction, modified ms medium with 4 mg/l picloram showin ... | 2006 | 17024590 |
| veratrum poisoning. | several species of the veratrum genus are associated with toxicity in humans and animals. the principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. these alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. increased stimulation, associated with the vagal nerve results in a reflex that causes the triad of responses known as the bezold-jarisch reflex: ... | 2006 | 16958554 |
| useful plants of dermatology. viii. the false hellebore (veratrum californicum). | plants have and continue to provide medicine with an abundance of pharmacologically interesting and useful chemicals. in recent years, cyclopamine, a steroidal alkaloid isolated from veratrum californicum, has been instrumental in dissecting the sonic hedgehog pathway. this brief report outlines cyclopamine's discovery with discussion of its potential application to clinical dermatology. | 2006 | 16546599 |
| isolation of teratogenic alkaloids by reversed-phase high-performance liquid chromatography. | reversed-phase high-performance liquid chromatography was used for both analytical and preparative separations of several steroidal alkaloids which occur in extracts of veratrum californicum. the inclusion of 0.1% trifluoroacetic acid in the mobile phase improved the efficiency of the chromatography and the solubility of the compounds in aqueous acetonitrile. nuclear magnetic resonance was used to assist the identification of the isolated steroidal alkaloids. the effect of the interaction of tri ... | 1984 | 6526920 |
| initial effects of ashfall from mount st. helens on vegetation in eastern washington and adjacent idaho. | extensive plant damage from the 18 may 1980 eruption of mount st. helens was largely restricted to acaulescent andprostrate dicot species in the ashfall area east of the cascade range (more than 150 kilometersfrom the vent). veratrum californicum, a large monocot, displayed widespread stem death through mechanical overloading of the plant's clasping leaves. the ash surface in this area presents new opportunities for both seeds and seed predators. | 1981 | 17794839 |
| effects of alkaloids of veratrum californicum on chick embryos. | | 1973 | 4737489 |
| teratogenic compounds of veratrum californicum (durand). 13. structure of muldamine. | | 1971 | 5135731 |
| teratogenic compounds of veratrum californicum (durand). vii. the structure of the glycosidic alkaloid cycloposine. | | 1969 | 4977212 |
| teratogenic compounds of veratrum californicum (durand). i. preparation and characterization of fractions and alkaloids for biologic testing. | | 1966 | 5919283 |