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1.
Phytomedicine ; 55: 191-199, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668429

RESUMO

BACKGROUND: Veratrum, hellebore is an important plant species of the Liliaceae family and jervine is the characteristic steroidal alkaloid constituent of Veratrum album. PURPOSE: In the current study, anti-inflammatory and antioxidant effects of jervine isolated from NH4OH-benzene extract of V. album rhizomes were investigated on CAR induced paw edema in rats. METHODS/STUDY DESIGN: In inflammatory study, 50, 100, 200 and 400  mg/kg doses of jervine, 25  mg/kg doses of DIC and IND were orally administered, and the volume of the foots were measured up to their knee arthrosis by plethismometer. After one hour of the oral administration of the all treatments, 0.1 ml of CAR solution (1%) was injected into the foot of the all rat groups and the volume of the foots were measured during 5 h after CAR injection. GPx, SOD, GR, MPO, CAT enzymes activities and GSH, LPO levels of the supernatants of paw homogenates and inflammation biomarkers such as TNF-α and IL-1ß in the rats serums were also estimated. RESULTS: According to the present results, jervine exerted 50.4-73.5% anti-inflammatory effects in carrageenan induced paw edema. Inflammation biomarkers such as TNF-α, IL-1ß and MPO that increased by CAR injection were suppressed by the administrations of all doses of jervine, IND and DIC. In all paw tissues, LPO levels as indicator of oxidative tissue damage were found to be high in CAR-treated group and it was found to be decreased in all doses of jervine. CONCLUSION: Jervine, DIC and IND reduced the negative effects of CAR due to increasing effects on the SOD, CAT, GSH, GPx and GR antioxidants.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Alcaloides de Veratrum/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/metabolismo , Carragenina/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Enzimas/metabolismo , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Ratos Sprague-Dawley , Rizoma/química , Fator de Necrose Tumoral alfa/metabolismo , Veratrum/química , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/isolamento & purificação
2.
Bioorg Med Chem Lett ; 26(19): 4735-4738, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27567371

RESUMO

Three new steroidal alkaloids 1-3, together with four known compounds 4-7, were isolated from the ethanol extract of Veratrum grandiflorum Loes. Their structures were elucidated by NMR (1D and 2D NMR) and MS spectroscopic data. The inhibition activities on Hedgehog (Hh) pathway were evaluated using a cell-based bioassay system (Shh-LIGHT 2 cells). The results showed that compounds 1-3 and 5 displayed inhibitory activities obviously with the IC50 values of 0.63-3.11µM. Among them, compound 5 showed the most prominent inhibition activity (IC50=0.63±0.02µM). Thus, these active alkaloids may be potent natural compounds as Hh pathway inhibitors for the treatment of various cancers.


Assuntos
Proteínas Hedgehog/antagonistas & inibidores , Alcaloides de Veratrum/farmacologia , Veratrum/química , Linhagem Celular , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Alcaloides de Veratrum/química , Alcaloides de Veratrum/isolamento & purificação
3.
Bioorg Med Chem ; 24(16): 3752-7, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27338657

RESUMO

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 the extraction efficiency for cyclopamine from root and rhizome by eight methods, and the associated biological activity in Shh-Light II cells using the Dual-Glo® Luciferase Assay System. Alkaloid recovery ranged from 0.39 to 8.03mg/g, with ethanol soak being determined to be the superior method for obtaining biologically active cyclopamine. Acidic ethanol and supercritical extractions yielded degraded or contaminated cyclopamine with lower antagonistic activity towards Hh signaling.


Assuntos
Alcaloides de Veratrum/farmacologia , Veratrum/química , Biomassa , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/isolamento & purificação
4.
Alkaloids Chem Biol ; 74: 201-32, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25845062

RESUMO

This survey on steroidal alkaloids of the Veratrum and Solanum family isolated between 1974 and 2014 includes 187 compounds and 197 references. New developments in the chemistry and biology of this family of natural products with a special focus on the medicinal relevance of the jervanine alkaloid cyclopamine are discussed.


Assuntos
Alcaloides de Solanáceas/química , Alcaloides de Solanáceas/farmacologia , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Diosgenina/química , Diosgenina/farmacologia , Humanos , Estrutura Molecular , Alcaloides de Veratrum/isolamento & purificação
5.
J Chromatogr Sci ; 53(7): 1092-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25547283

RESUMO

Veratramine (VAM) is the major lipid-soluble alkaloid existing in Veratrum nigrum L. that has been demonstrated to exert neurotoxic effects. To better understand the potential mechanism of neurotoxicity of VAM, VAM-induced DNA damage was measured in the cerebellum and cerebral cortex of mice after a 7-day repetitive oral dose by using single-cell gel electrophoresis (comet assay). A method based on high-performance liquid chromatography-electrospray ionization tandem mass spectrometry was developed for the determination of VAM and its in vivo and in vitro metabolites, to establish the potential correlation between metabolites and neurotoxicity. In vitro experiment was carried out using rat liver microsomes, whereas the in vivo study was conducted on rats at a single dose of 3 mg/kg. The results showed that VAM caused DNA damage in the cerebellum and cerebral cortex of mice in a dose-dependent manner. Phenyl mono-oxidation, sulfate conjugation and phenyl di-oxidation were proposed to be the main in vivo metabolic pathways of VAM, whereas the major in vitro metabolic pathways were phenyl mono-oxidation, hydroxylation and methylation. Phenyl-oxidation reaction was likely to be associated with reactive oxygen species production, leading to the DNA damage in the mouse brain.


Assuntos
Encéfalo/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Alcaloides de Veratrum/metabolismo , Alcaloides de Veratrum/toxicidade , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Espectrometria de Massas por Ionização por Electrospray/métodos , Veratrum/química , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/isolamento & purificação
6.
Nat Prod Commun ; 8(8): 1059-64, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24079166

RESUMO

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 for the four steroidal alkaloids which have been released to the public database MassBank.jp. The reported Soxhlet extraction method nearly triples the recovery of steroidal alkaloids from V. californicum.


Assuntos
Alcaloides de Veratrum/isolamento & purificação , Veratrum/química , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Alcaloides de Veratrum/química
7.
J Ethnopharmacol ; 141(1): 183-6, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22366682

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Veratrum patulum L. (Liliaceae) is used as one source of the Chinese traditional drug "Lilu" which has been used in the treatment of aphasia arising from apoplexy, wind type dysentery, headache, etc. for thousands of years. AIM OF THE STUDY: To evaluate the antithrombotic effect of Veratrum patulum L. (Liliaceae) total steroidal alkaloids (VpA) and explore the potential mechanisms. MATERIALS AND METHODS: The antithrombotic effect of VpA was evaluated in two experimental thrombosis models in rat. The potential antithrombotic mechanisms of VpA were explored by determining the coagulation parameters and platelet aggregation induced by various agonists. Cutting-tail rat model was used to evaluate the influence of VpA on bleeding time. RESULTS: VpA significantly inhibit the formation of arterial and venous thrombosis and showed different inhibitory effect on the platelet aggregation induced by various agonists with the following potency order: collagen>ADP>thrombin. VpA showed no influence on the coagulation parameters in rat. But VpA decreased the cutting-tail bleeding time in rat. CONCLUSION: VpA possess antithrombotic effect on venous and arterial thrombosis. The antithrombotic effect of VpA is due to its inhibition to platelet aggregation, especially induced by collagen.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fibrinolíticos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Trombose/prevenção & controle , Alcaloides de Veratrum/farmacologia , Veratrum , Difosfato de Adenosina , Animais , Anticoagulantes/química , Anticoagulantes/isolamento & purificação , Tempo de Sangramento , Colágeno , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Feminino , Fibrinolíticos/química , Fibrinolíticos/isolamento & purificação , Masculino , Fitoterapia , Raízes de Plantas , Plantas Medicinais , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/isolamento & purificação , Testes de Função Plaquetária , Ratos , Ratos Sprague-Dawley , Rizoma , Trombina , Trombose/sangue , Fatores de Tempo , Veratrum/química , Alcaloides de Veratrum/química , Alcaloides de Veratrum/isolamento & purificação
8.
Chin J Cancer ; 30(7): 472-81, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21718593

RESUMO

The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1(neo/neo) and K14cre:SmoM2(YFP)). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.


Assuntos
Carcinoma Basocelular/patologia , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/patologia , Carga Tumoral/efeitos dos fármacos , Alcaloides de Veratrum/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Embrionárias/citologia , Proteínas Hedgehog/antagonistas & inibidores , Camundongos , Neurônios Motores/citologia , Plantas Medicinais/química , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor Smoothened , Solubilidade , Tartaratos/sangue , Tartaratos/farmacologia , Veratrum/química , Alcaloides de Veratrum/sangue , Alcaloides de Veratrum/isolamento & purificação
9.
Z Naturforsch C J Biosci ; 65(3-4): 195-200, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20469637

RESUMO

Twelve steroidal alkaloids were isolated from four populations of Veratrum lobelianum Bernh. and Veratrum nigrum L. Full NMR data for veralosinine (1), and extensive 1H NMR data for veralosine (3) and teinemine (5) are presented here for the first time. (+/-)-15-O-(2-Methylbutyroyl)germine (10) is undescribed up to now. The antiproliferative activities of veranigrine, veralosinine, and neogermitrine have shown that they are a perspective for further studies.


Assuntos
Divisão Celular/efeitos dos fármacos , Alcaloides de Veratrum/isolamento & purificação , Veratrum/química , Animais , Bulgária , Leucemia L5178/patologia , Espectroscopia de Ressonância Magnética , Medicina Tradicional , Camundongos , Modelos Moleculares , Mongólia , Fitosteróis/farmacologia , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologia
10.
Phytother Res ; 24(6): 821-6, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20013819

RESUMO

Ten steroidal alkaloids - cyclopamine, veratramine, jervine, 3, 15-diangyloylgermine, 3-angyloylzygadenine, 3-veratroyl zygadenine, 15-veratroylgermine, germine, veratrosine and pseudojervine - from Veratrum dahuricum, together with the ethanol extract and total alkaloids, were evaluated for their antitumor and antiplatelet activities. Cyclopamine, veratramine and germine significantly inhibited the hedgehog pathway in NIH/3T3 cells. Cyclopamine exerted a potent inhibitory effect against the growth of PANC-1 tumors in mice, with inhibition rates of 40.64%, 44.37%, 46.77% at doses of 5.0, 15.0 and 50.0 mg kg-1, respectively. Veratroylgermine was found to produce the strongest inhibition against the platelet aggregation induced by arachidonic acid, with inhibition rate of 92.0% at 100 microM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Alcaloides de Veratrum/farmacologia , Veratrum/química , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Coelhos , Alcaloides de Veratrum/isolamento & purificação
11.
J Appl Toxicol ; 29(5): 414-21, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19301244

RESUMO

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. with purified cyclopamine for toxicokinetic analysis. Another four groups of ewes were dosed orally twice daily with 0.88 g/kg of V. californicum on GD 13, 14 or 15 or consecutively on GD days 13-15. Pregnancy and pre-partum fetal malformations were determined by ultrasound imaging on GD 60. At parturition lambs were assessed for gross malformations. The elimination half-life of cyclopamine in ewes was determined to be 1.1 +/- 0.1 h. The rapid clearance of cyclopamine indicates that ingestion of V. californicum must occur during a very narrow window for synophthalmia formation to occur. Ewes dosed with V. californicum on GD 13 or 14 had lambs with various craniofacial malformations including cyclopia, maxillary dysplasia and mandibular micrognathia. Ewes dosed on GD 15 delivered normal lambs. Ewes dosed consecutively on GD 13-15 were not pregnant at GD 60 and Veratrum-induced embryonic death was assumed to be the cause. Interestingly, lambs with cyclopia were smaller, under-developed and appeared premature even though their twin appeared fully developed. Initial evaluations suggest this was due to placental dysplasia.


Assuntos
Holoprosencefalia/induzido quimicamente , Exposição Materna/efeitos adversos , Ovinos/anormalidades , Teratogênios/toxicidade , Alcaloides de Veratrum/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Idade Gestacional , Holoprosencefalia/embriologia , Raízes de Plantas/química , Gravidez , Ovinos/embriologia , Teratogênios/isolamento & purificação , Teratogênios/farmacocinética , Fatores de Tempo , Veratrum/química , Alcaloides de Veratrum/isolamento & purificação , Alcaloides de Veratrum/farmacocinética
12.
Zhongguo Zhong Yao Za Zhi ; 33(7): 791-2, 2008 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-18589783

RESUMO

OBJECTIVE: To develop an HPLC-ELSD method for determination of vetatramine. in Veratrum nigrum. METHOD: The analy fical column was Shim-pack ODS - C18 (4.6 mm x 250 mm, 4 microm) column, the mobile phase was acetonitrile-water (containing 0.1% triethylamine) (50:50), at a flow rate of 0.8 mL x min(-1). The temperature of drift tube was 90 degrees C and the gas flow was at the rate of 2.5 L x min(-1). RESULT: The calibration curve was linear in the range of 0.36-3.6 microg (r = 0.999 8). The average recovery was 100.9% (RSD 2.3%, n = 6). The contents of veratramine in Veratrum nigrum. from the ten different sources were determined. CONCLUSION: The method may be used as a accurate and reproducible way to determine the content of veratramine in V. nigrum.


Assuntos
Alcaloides de Veratrum/análise , Veratrum/química , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Alcaloides de Veratrum/isolamento & purificação
14.
Mol Divers ; 9(1-3): 41-4, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15789550

RESUMO

A collection of plants from the country of Georgia (Galanthus caucasicus, Magnolia obovata, Cocculus laurifolius, and Veratrum lobelianum) has been studied for their alkaloid content. Our studies led to the isolation and identification of 24 alkaloids, three of which are being identified and reported for the first time.


Assuntos
Alcaloides/química , Cocculus/química , Galanthus/química , Magnolia/química , Fenóis/química , Extratos Vegetais/química , Alcaloides de Veratrum/química , Alcaloides/isolamento & purificação , Georgia , Espectrometria de Massas , Estrutura Molecular , Fenóis/isolamento & purificação , Alcaloides de Veratrum/isolamento & purificação
16.
Proc Soc Exp Biol Med ; 192(2): 153-6, 1989 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2813445

RESUMO

Logistic and biologic aspects of three separate means of administration of cyclopamine for experimental induction of terata or embryonic death in sheep were examined. Oral capsule administration of crystalline cyclopamine is logistically simple and biologically effective, but costly in terms of amount of compound required. Embryos were affected in five of seven ewes dosed cyclopamine orally at higher levels (four nonpregnant and one with cyclopia). Intramuscular administration of cyclopamine dissolved in ethanol was logistically simple but without biologic effect at levels tested. Three of three treated ewes had normal offspring. Osmotic minipump administration of powdered cyclopamine suspended in propylene glycol was logistically unsatisfactory with serious delivery complications. Osmotic minipump administration of cyclopamine dissolved in ethanol was logistically very satisfactory, and one ewe among three treated animals was nonpregnant at term. There were no nonpregnant ewes nor deformed offspring in 17 controls.


Assuntos
Prenhez/fisiologia , Ovinos/fisiologia , Teratogênios/administração & dosagem , Alcaloides de Veratrum/administração & dosagem , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Morte Fetal , Bombas de Infusão , Injeções Intramusculares , Gravidez , Alcaloides de Veratrum/isolamento & purificação , Alcaloides de Veratrum/toxicidade
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