Blue Cohosh Research Articles

Teratogenic Effects of Blue Cohosh (Caulophyllum thalictroides) in Japanese Medaka (Oryzias latipes) are Mediated through GATA2/EDN1 Signaling Pathway

Blue cohosh (Caulophyllum thalictroides) (BC) has been used widely to induce labor and to treat other uterine complications [1]. However, the safety and effectiveness of this herbal product has not yet been evaluated by the Food and Drug Administration (FDA) of the USA. Several conflicting reports indicated that the root extract of BC is a teratogen, and by some unknown mechanisms, is able to induce cardiovascular malfunctions in newborn babies. To understand the mechanism we have used Japanese medaka (Oryzias latipes) embryo-larval development as the experimental model and methanolic extract of BC root as the teratogen. The embryo mortality, hatching efficiency, morphological abnormalities in craniofacial and cardiovascular systems and several biochemical parameters are considered for the evaluation of BC toxicity. Our results indicate that BC is able to disrupt cardiovascular and craniofacial cartilage development in medaka embryo in a dose and developmental stage-specific manner. Moreover, embryos precirculation are to some extent more resistant to BC than ones with circulation. Biochemical analyses are unable to establish an effect of BC in total protein, RNA and DNA contents and in the expression of emx2, en2, iro3, otx2, shh, wnt1 and zic5 mRNAs in circulating embryos. However, in precirculating embryos, total RNA content and shh mRNA expression was reduced after BC treatment. By using subtractive hybridization, we are able to demonstrate that gata2 mRNA was differenzially expressed in the circulating embryos after BC treatment. Further analysis identified the rapid expression of gata2 mRNA followed by preproendothelin1 (edn1) mRNA by BC which might be able to induce vasoconstriction and cardiovascular defects in medaka embryo. We therefore conclude that cardiovascular disruption in medaka embryogenesis by BC is probably mediated through Gata2-Edn1 signaling pathway. Acknowledgements: This work was supported by the United States Food and Drug Administration (FDA) 5U01FD002071–09, National Center of Natural Product Research, Environmental Toxicology Research Program and Department of Pharmacology of the University of Mississippi.

Detection of ecological hybrid inviability in a pair of sympatric phytophagous ladybird beetles (Henosepilachnaspp.)

AbstractEcological speciation is a process by which reproductive isolation evolves as the result of divergent natural selection between populations inhabiting distinct environments or exploiting alternative resources. Ecological hybrid inviability provides direct evidence for ecological speciation. To detect ecological hybrid inviability, we examined survival rates to the second instar of F1 hybrids and backcross hybrids in a pair of sympatric phytophagous ladybird beetles,Henosepilachna niponicaLewis andHenosepilachna yasutomiiKatakura (Coleoptera: Coccinellidae: Epilachninae), reared on their respective host plants, thistle [Cirsium alpicolaNakai (Asteraceae)] and blue cohosh [Caulophyllum robustumMaxim. (Berberidaceae)], and on a common food plant, Japanese nightshade [Solanum japonenseNakai (Solanaceae)]. Hybrid larvae reared on leaves of the Japanese nightshade always had high rates of survival, irrespective of the crossing type of their parents, suggesting a lack of intrinsic hybrid inviability between the two species. In contrast, survival rates on thistle and blue cohosh varied greatly. On blue cohosh, the survival rate of F1 hybrids was nearly as high as that ofH. yasutomii, but on thistle, survival was significantly lower than ofH. niponica. Survival rates of backcross hybrids on the two host plants were intermediate between those of the parents, showing a reversed rank order of different types of backcross hybrids on the two food plant species. These results suggest that ecological hybrid inviability exists betweenH. niponicaandH. yasutomii, although the two species do not show intrinsic hybrid inviability. Thus, our study supports the hypothesis thatH. niponicaandH. yasutomiiunderwent ecological speciation by divergent selection.

Medicinal understory herbaceous species cultivated under different light and soil conditions in maple forests in southern Québec, Canada

Many northern hardwood understory plants have medicinal properties but their cost of production under conventional cultivation practices is fairly high. Therefore wild harvesting continues putting the natural populations at risk. Their cultivation in a forest farming system seems a promising alternative. This study was aimed at assessing the impact of canopy opening and soil fertility on growth and active component production of four medicinal plants: black cohosh (Actaea racemosa), wild ginger (Asarum canadense), blue cohosh (Caulophyllum thalictroides) and bloodroot (Sanguinaria canadensis). Rhizome sections were planted in two sugar maple forests. Mortality and total leaf area were monitored during 3 years, while subplots were harvested at the end of the second year for biomass and active component analyses. Multiple regressions indicated that all species responded more to acidity related elements (pH, Al, Al + H, Fe, Zn) than to soil fertility (Ca, K, Mg, P, C/N, base saturation and cation exchange capacity). This suggests that adjusting the pH by liming could be appropriate. Growth increased with irradiance, except for blue cohosh, indicating that forest openings could also be part of an appropriate forest management plan for their cultivation. While active component concentrations of rhizomes and roots increased in conditions that negatively affected growth, such as low pH, soil fertility or light availability, their total active component content exhibited responses that were similar to those of the growth variables. Thus, it seems that soil and light conditions that favour the growth of these medicinal plants also favour their total yield in active components.

Triterpene Glycosides from the Underground Parts of Caulophyllum thalictroides

A total of 22 triterpene glycosides, including 10 new compounds (1-10), were isolated from the underground parts of Caulophyllum thalictroides. The structures of the new glycosides were determined on the basis of extensive spectroscopic analyses, including two-dimensional (2D) NMR data, and of hydrolytic cleavage followed by chromatographic or spectroscopic analyses. All 22 compounds were evaluated for cytotoxicity against HL-60 human leukemia cells. The triterpene monodesmosides based on oleanolic acid (1 and 11-16) showed cytotoxic activity against HL-60 cells with IC(50) values that ranged from 3.4 to 15.9 microg/mL.

Teratogenic Effects of Blue Cohosh is Mediated through GATA2 Signaling Pathway

Blue cohosh (Caulophyllum thalictroides) (BC) is a perennial herb used by Native American Indian women to induce labor and for the treatment of other uterine complications. Several studies indicated that BC was not absolutely safe for the fetus and able to induce perinatal stroke and ischemia in newborn babies [1]. A recent chemical analysis identified 15 alkaloid-triterpene compounds present in BC [2] and some of them are potential teratogens. We used Japanese medaka (Oryzias latipes) embryo-larval development as our experimental model to verify the teratogenic potency of BC during embryogenesis. We observed that BC was able to induce cardiovascular defects in medaka embryo during development; however, total protein, RNA and several transcription factor mRNAs (emx2, en2, iro3, otx2, shh1, wnt1 and zic5) which were expressed in central nervous system (CNS) of medaka embryo during embryogenesis remained unaltered. Further, we have used subtractive hybridization technique to identify BC-sensitive genes in medaka embryogenesis. We have observed that transcription factor GATA2 was over expressed by BC and in situ hybridization analysis indicated that GATA2 over expression was occurred in CNS. Analysis by semi-quantitative reverse transcriptase polymerase Chain reaction (rt-PCR) indicated that GATA2 mRNA expression was very rapid (significantly increased within 15 min of BC exposure). We predict that teratogenic effects of BC are due to over expression of GATA2 gene that can induce the expression of endothelin-1 mRNA in the cerebral microvessels and peripheral vessels, and thus cause dysfunction of cerebrovascular and cardiovascular system of Japanese Medaka during development.

Inhibition of Cytochrome P450 by Constituents from Blue Cohosh (Caulophyllum thalictroides)

Inhibition of Cytochrome P450 by Constituents from Blue Cohosh (Caulophyllum thalictroides)

Alkaloids and Saponins as Cytochrome P450 Inhibitors from Blue Cohosh (Caulophyllum thalictroides) in anin vitroAssay

Blue cohosh, Caulophyllum thalictroides (L.) Michx. is a popular herb, roots and rhizomes of which have been extensively used for women's health. Alkaloids and saponins are considered to be responsible for its pharmacological effects. In this investigation the methanolic extract of the roots of blue cohosh, the alkaloidal fraction and isolated constituents were evaluated for their inhibition of major drug metabolizing cytochrome P450 (CYP450) enzymes. The methanolic extract did not show any effect but the alkaloidal fraction showed a strong inhibition of CYP 2C19, 3A4, 2D6, and 1A2 (>80% inhibition at 100 microg/mL) with IC50 values in the range of 2-20 microg/mL. Among the isolated alkaloids, a piperidine-type alkaloid (caulophyllumine B) and three lysine-derived alkaloids (O-acetlybaptifolin, anagyrine, and lupanine) inhibited these enzymes to various extents (IC50:2.5-50 microM). N-Methylcytisine weakly inhibited CYP3A4 only (32% inhibition at 100 microM). An equimolar mixture of alkaloids exhibited a more pronounced inhibitory effect on all four enzymes as compared to the isolated alkaloids. Among the saponins, caulosides C and D inhibited CYP3A4 at the highest test concentration of 100 microM (43% and 35% inhibition, respectively). Other enzymes were not affected. This in vitro study indicates that dietary supplements containing blue cohosh may pose a risk of drug-drug interactions if taken with other drugs or herbs, metabolism of which involves CYP450 enzymes.

Research Article: Pharmacological effects of the aqueous extract of Caulophyllum thalictroides (blue cohosh) on isolated Mus musculus uteri

The roots and rhizomes of Caulophyllum thalictroides (blue cohosh), traditionally used as an aid for childbirth, contain several active alkaloids and saponins, which act directly on uterine smooth muscle resulting in an oxytocic response. The historical use of this herbal supplement has been well documented, but there are few clinical studies addressing its efficacy and potential side effects. This research investigated the physiological and pharmacological responses of blue cohosh on isolated strips of murine uterine tissue. Uterine horns from mice were suspended in a smooth muscle bath and exposed to the aqueous extract of blue cohosh (doses ranging from 0.037–23.8 mg). All tissues showed an increase in the strength of contractile force, the frequency of the contraction, and basal tonus. Contractile forces were significantly greater with higher doses (P = 0.0027). The stages of estrous were determined by vaginal smears and dose-dependency was consistent in all stages of estrous observed (diestrus, estrus, metestrus). Blocking experiments with d-tubocuranine, a nicotinic receptor antagonist, were inconclusive as decreases in contractile responses were not statistically different from the observed fatigue following control cumulative dosing.

Vegetative Propagation of Five Northern Forest Understory Plant Species from Either Rhizome or Stem Sections

Five understory plants, Asarum canadense L., Caulophyllum thalictroides (L.) Michx., Sanguinaria canadensis L., Trillium grandiflorum (Michx.) Salisb., of the Northeastern hardwood forests, and Oplopanax horridus (Sm.) Miq., of Western North American temperate forests, are of particular interest for horticultural and natural medicinal products industries. A rapid and efficient propagation method was needed to reproduce these plants vegetatively. To achieve this, the effect of 1000 mg·L−1 (for herbaceous species) or 3000 mg·L−1 (for O. horridus) auxin (IBA) and/or cytokinin (kinetin) on the growth of rhizome (for A. canadense, C. thalictroides, S. canadensis, T. grandiflorum) or stem sections (for O. horridus) was investigated. Nontreated controls were included for each species and an additional control with an intact apical bud was included for A. canadense, S. canadensis, and T. grandiflorum. No vegetative propagation was obtained for T. grandiflorum. Survival of O. horridus and C. thalictroides propagating units was 60% to 80% and 90% to 100%, respectively, and both rooted well even in absence of growth regulators. Asarum canadense produced two times and S. canadensis three to four times more roots when treated with the IBA + kinetin or the IBA treatment, respectively, compared with the control rhizome sections without an apical bud. For these two species, the presence of an apical bud enhanced survival and/or shoot emergence and those rhizome sections produced on average more biomass than the other treatments. Our results showed that either rhizome or stem sections can provide an efficient method to propagate A. canadense, C. thalictroides, O. horridus, and S. canadensis and thus reduce pressure on wild populations.

ChemInform Abstract: Alkaloids and Saponins from Blue Cohosh.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Blue Cohosh's Teratogenic Effect is Restricted to the Cardiovascular System in Medaka

Blue Cohosh's Teratogenic Effect is Restricted to the Cardiovascular System in Medaka

Alkaloids and Saponins in Dietary Supplements of Blue Cohosh (Caulophyllum thalictroides)

Preparations of blue cohosh (Caulophyllum thalictroides) have been used traditionally by Native Americans for medicinal purposes. Dietary supplements containing dried roots or extracts of blue cohosh rhizomes are available as dietary supplements. The safety and efficacy of these preparations have not been systematically evaluated. Recent studies indicate that ingestion of specific alkaloids in blue cohosh preparations can produce birth defects and neonatal heart failure. Blue cohosh also contains saponins, which may be responsible for uterine-stimulating effects. We determined the amounts of major alkaloids and saponins in preparations of blue cohosh by high-performance liquid chromatography (HPLC). Alkaloids and saponins were monitored with a photodiode array detector and an evaporative light-scattering detector, respectively. Profiles were compared with those of authenticated blue cohosh root extracts. Identities of the alkaloids and saponins were confirmed by HPLC/mass spectrometry and nuclear magnetic resonance spectrometry. Calculations based on the results of analyses of dietary supplements showed that maximum daily intake of alkaloids and saponins will vary with the form (e.g., root, liquid extract) and doses recommended in product labeling. Intakes may vary from < 1 to 75 mg/day for alkaloids and from about 9 to 420 mg/day for saponins.

Alkaloids and saponins from blue cohosh

Blue cohosh, Caulophyllum thalictroides (L.) Michx. (Berberidaceae), is used primarily to cure menstrual disturbances and to ease childbirth. Alkaloids and saponins are considered to be responsible for its pharmacological activity. A detailed phytochemical investigation of blue cohosh resulted in the isolation of 15 compounds belonging to the alkaloids and the triterpene saponins. The structures of two alkaloids, caulophyllumines A ( 1) and B ( 2) and a saponin, cauloside H ( 3) both previously unknown were determined by spectroscopic techniques, including by 1- and 2-D NMR as well as by chemical analysis.

Induction of Labor with Homeopathy: A Case Report

Homeopathic preparations of blue cohosh (Caulophyllum thalictroides) and black cohosh (Actaea racemosa [formerly Cimicifuga racemosa]) have been used around the world for induction and augmentation of labor. There are few clinical studies examining these preparations, and the evidence for their safety and efficacy is largely anecdotal. More research needs to be done to determine whether homeopathy is a potentially viable alternative to oxytocin and prostaglandins for labor induction.

Neonatal Epilepsy Associated with Maternal Ingestion of Blue Cohosh

ABSTRACTAimTo describe a case of neonatal epilepsy associated with maternal ingestion of blue cohosh.Clinical detailsA 32‐year‐old female consumed a mixture of blue cohosh, raspberry leaf and squaw vine for 4 days in late pregnancy to hasten the onset of labour. After delivery, the neonate showed signs consistent with status epilepticus which was confirmed by electroencephalogram and treated accordingly.OutcomeThe neonatal epilepsy settled with conventional treatment and there were no long‐term sequelae.ConclusionEvidence of adverse effects associated with complementary and alternative medicines continues to accumulate. Patients must be specifically questioned about their use of complementary and alternative medicines. This case report suggests a possible association between blue cohosh and neonatal epilepsy.

Concentrations of the alkaloids magnoflorine, N‐methylcystine and baptifoline in samples of blue cohosh

Preparations of roots of Blue Cohosh (Caulophyllum thalictroides) have been promoted for their estrogen-like benefits and are sold as dietary supplements in the form of powder, tablet and liquid. The safety and efficacy of such preparations have not been systematically evaluated. Recent studies indicate that ingestion of Blue Cohosh can produce birth defects and neonatal heart failure in humans. These effects may be due to some of the alkaloids present in the plant preparations. Two such alkaloids, baptifoline and N-methylcytisine, possess anti-inflammatory and mutagenic properties. We purified magnoflorine, N-methylcytisine and baptifoline from rhizomes of authenticated plant material and used these alkaloids as external standards during the analysis of commercial samples. Rhizomes of authenticated Blue Cohosh were obtained from Botanical Liaisons, Boulder CO. Samples of Blue Cohosh in powder, capsule and liquid forms were obtained from commercial sources. The rhizomes were powdered in a blender, sieved through a #60 sieve and extracted in methanol (5g/25mL). The contents of 10 capsules were mixed and 0.5g extracted in 10mL methanol. Liquid samples were diluted 1:10 with methanol. All samples were analyzed by HPLC using an XTerra Phenyl reversed phase HPLC column with a gradient mobile phase consisting of water and acetonitrile, each with 2 mM ammonium bicarbonate and 0.1% ammonium hydroxide. All three alkaloids were detected in all samples with magnoflorine present in the highest concentrations and baptifoline in the lowest concentrations.

Field‐cage experiments on host fidelity in a pair of sympatric phytophagous ladybird beetles

AbstractUsing field cages, we tested the hypothesis that two phytophagous ladybird beetles, Henosepilachna niponica (Lewis) and Henosepilachna yasutomii Katakura (Coleoptera: Coccinellidae: Epilachninae), are reproductively isolated from each other by their host fidelity alone. We planted host plants of the two species [the thistle Cirsium alpicola Nakai (Asteraceae) for H. niponica and the blue cohosh, Caulophyllum robustum Maxim. (Berberidaceae), for H. yasutomii] in 7 × 7 m cages (BT cages), and planted the two host plants and the beetles’ common food plant, the Japanese nightshade, Solanum japonense Nakai (Solanaceae), in other cages (BJT cages). We then released overwintered reproducing beetles into these cages and recorded their dispersal, the distribution of egg masses, and the incidence of copulations. In BT cages, the beetles moved almost exclusively between their own host plants, and all females laid eggs exclusively on their own host plants. In BJT cages, the beetles moved between their own host plants and the Japanese nightshade, resulting in occasional interspecific mating on the same nightshade plant. Females of both species laid eggs on their own host plants as well as on the Japanese nightshade. These results indicate that host fidelity functions as a strong barrier against gene flow between H. niponica and H. yasutomii. However, this barrier can easily be broken down if a third plant species bridges the beetle populations.

Rich mesic forests: Edaphic and physiographic drivers of community variation in western Massachusetts

Rich Mesic Forest, a Northeastern variant of the species-rich Mixed Mesophytic Forest association of eastern North America, is an Acer saccharum-dominated forest type typically associated with calcareous bedrock and nutrient-rich, mull soils. Rich Mesic Forest (RMF) is a priority for conservation in the Northeast due to its limited areal extent, high plant species richness, and numerous rare taxa, yet the community characteristics and environmental correlates of this forest type are incompletely understood. This study undertook a quantitative classification of RMF of the northeastern edge of the Berkshire Plateau in western Massachusetts. Cluster analysis of data from ten sites identified two vegetation types within the RMF community, the Acer saccharum–Allium tricoccum–Caulophyllum thalictroides Type (AAC) and the Acer saccharum–Dicentra cucullaria–Polystichum acrostichoides Type (ADP); in addition, two subtypes were distinguished within ADP. Ordination of vegetation data using detrended correspondence analysis identified increased soil pH and calcium concentration as key environmental factors associated with variation within RMF and differentiation of RMF from the typical northern and transition hardwoods vegetation of the region. On sites with high soil pH and nutrients, vegetation variation was primarily associated with physiography, particularly the presence of exposed bedrock and solar insolation levels as controlled by slope and aspect. Occurrences of RMF on steep sites with frequent bedrock exposures and high insolation provide habitat for uncommon plant species reaching their northeastern range limits in the Northeast, and are of particular interest for biodiversity conservation. Comparisons between the results of this study in western Massachusetts and prior research on Mesophytic Forests in other regions of eastern North America illustrate a striking constancy in species composition, with over 70% of common species in Mesophytic Forests of the Southeast and Midwest also being recorded in RMF in our study region.

More on Blue Cohosh and Perinatal Stroke

More on Blue Cohosh and Perinatal Stroke

Determination of saponins and alkaloids in Caulophyllum thalictroides (blue cohosh) by high-performance liquid chromatography and evaporative light scattering detection.

The roots of Caulophyllum thalictroides, traditionally used for the treatment of menstrual difficulties and as an aid in childbirth, contain saponins, which are considered to be responsible for the uterine stimulant effects, together with teratogenic alkaloids. An HPLC method has been developed which permits the determination of the triterpene saponins in the plant and also the separation of four alkaloids. The best results were obtained with a C-12 stationary phase using ammonium acetate buffer (pH 8.0) and acetonitrile as mobile phase. Owing to their low UV absorbance, the saponins were detected by evaporative light scattering, whereas the alkaloids were monitored by UV at 310 nm. The identities of the compounds were confirmed in an LC-MS experiment. Different plant samples and commercial products have been analysed using the described method, and remarkable qualitative and quantitative variations were revealed. Comparing the daily uptake of total saponins, a difference of greater than 100-fold was observed within the various products; the alkaloid content on the other hand was more uniform.