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1.
Chem Biodivers ; 17(2): e1900473, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31961474

RESUMO

Veratrum plant contains a family of compounds called steroidal alkaloids which have been previously reported to cause DNA damage and blood pressure decrease in vivo. In this study, the antihypertensive effects and DNA damage in brain cells of 12 steroidal alkaloids separated from Veratrum plant were all evaluated to develop a relationship among chemical structure, antihypertensive activity and neurotoxicity by utilization of chemical principal component analysis (PCA) and hierarchical cluster analysis (HCA). Twelve steroidal alkaloids markedly reduced high blood pressure of hypertensive mice and also similarly induced varying degrees of DNA single-strand breaks in mouse cerebellum and cerebral cortex after oral administration. On the basis of the PCA and HCA results, it was suggested that the 3-carboxylic esters and benzene group play a core role in the DNA damage of brain cells, while more hydroxy groups in the A-ring and B-ring structure of jervine-type alkaloid led to stronger antihypertensive activity. The primary structure, activity and neurotoxicity relationship were discussed briefly.


Assuntos
Anti-Hipertensivos/química , Alcaloides de Veratrum/química , Veratrum/química , Administração Oral , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Análise por Conglomerados , Dano ao DNA/efeitos dos fármacos , Camundongos , Extratos Vegetais/química , Análise de Componente Principal , Relação Estrutura-Atividade , Veratrum/metabolismo , Alcaloides de Veratrum/farmacologia
2.
Fitoterapia ; 137: 104281, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31381957

RESUMO

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.


Assuntos
Alcaloides/química , Esteroides/química , Veratrum/química , Alcaloides/isolamento & purificação , Proteínas Hedgehog/antagonistas & inibidores , Idaho , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Componentes Aéreos da Planta/química , Rizoma/química , Estações do Ano , Esteroides/isolamento & purificação , Alcaloides de Veratrum
3.
Gene ; 712: 143962, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31288057

RESUMO

Veratrum nigrum is protected plant of Melanthiaceae family, able to synthetize unique steroidal alkaloids important for pharmacy. Transcriptomes from leaves, stems and rhizomes of in vitro maintained V. nigrum plants were sequenced and annotated for genes and markers discovery. Sequencing of samples derived from the different organs resulted in a total of 108,511 contigs with a mean length of 596 bp. Transcripts derived from leaf and stalk were annotated at 28%, and 38% in Nr nucleotide database, respectively. The sequencing revealed 949 unigenes related with lipid metabolism, including 73 transcripts involved in steroids and genus-specific steroid alkaloids biosynthesis. Additionally, 3203 candidate SSRs markers we identified in unigenes with average density of one SSR locus every 6.2 kb sequence. Unraveling of biochemical machinery of the pathway responsible for steroidal alkaloids will open possibility to design and optimize biotechnological process. The transcriptomic data provide valuable resources for biochemical, molecular genetics, comparative transcriptomics, functional genomics, ecological and evolutionary studies of V. nigrum.


Assuntos
Alcaloides/biossíntese , Regulação da Expressão Gênica de Plantas , Esteroides/biossíntese , Transcriptoma , Veratrum/metabolismo , Mapeamento de Sequências Contíguas , DNA Complementar/metabolismo , Biblioteca Gênica , Ontologia Genética , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Repetições de Microssatélites , Anotação de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Análise de Sequência de RNA
4.
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
5.
Biol Pharm Bull ; 42(1): 1-9, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30381617

RESUMO

Veratrum maackii (VM), a perennial plant in the Melanthiaceae family, has anti-hypertensive, anti-cholinergic, anti-asthmatic, anti-tussive, anti-fungal, anti-melanogenesis, and anti-tumor activities. Here, we investigated the therapeutic effect of VM on benign prostatic hyperplasia (BPH) in human normal prostate cell line (WPMY-1) and a testosterone propionate-induced BPH animal model. WPMY-1 cells were treated with VM (1-10 µg/mL) and testosterone propionate (100 nM). BPH in rats was generated via daily subcutaneous injections of testosterone propionate (3 mg/kg) dissolved in corn oil, for 4 weeks. VM (150 mg/kg) was administered daily for 4 weeks by oral gavage concurrently with the testosterone propionate. All rats were sacrificed and the prostates were dissected, weighed, and subjected to histological, immunohistochemical, and biochemical examinations. Immunoblotting experiments indicated that WPMY-1 cells treated testosterone propionate had increased expression of prostate specific antigen (PSA) and androgen receptor (AR), and treatment with VM or finasteride blocked this effect. In rat model, VM significantly reduced prostate weight, prostatic hyperplasia, prostatic levels of dihydrotestosterone (DHT), and expression of proliferation markers such as proliferating cell nuclear antigen (PCNA) and cyclin D1, but increased the expression of pro-apoptotic Bcl-2-associated X protein (Bax) and the cleavage of caspase-3. VM administration also suppressed the testosterone propionate-induced activation of nuclear factor-kappaB (NF-κB). Our results indicate that VM effectively represses the development of testosterone propionate-induced BPH, suggesting it may be a useful treatment agent for BPH.


Assuntos
Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Propionato de Testosterona/toxicidade , Veratrum , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
6.
Molecules ; 23(9)2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30200443

RESUMO

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine whether additional alkaloids in the extracts contribute to Hh signaling inhibition, the concentrations of these four alkaloids present in extracts were replicated using commercially available standards, followed by comparison of extracts to alkaloid standard mixtures for inhibition of Hh signaling using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts are capable of inhibiting Hh signaling.


Assuntos
Alcaloides/farmacologia , Proteínas Hedgehog/metabolismo , Transdução de Sinais/efeitos dos fármacos , Veratrum/química , Animais , Biomassa , Camundongos , Células NIH 3T3 , Extratos Vegetais/farmacologia , Folhas de Planta/química , Raízes de Plantas/química , Caules de Planta/química , Padrões de Referência
7.
Clin Dermatol ; 36(3): 399-419, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29908582

RESUMO

The plant and mushroom kingdoms have species used for intoxication, inebriation, or recreation. Some of these species are toxic. Given that many of these plants or substances are illegal and have histories of abuse, much of the research regarding therapeutic application is based on basic science, animal studies, and traditional use. This review examines Cannabis, Euphorbia, Ricinus, Podophyllum, Veratrum, mushrooms, and nightshades, along with resveratrol and cocaine as they relate to dermatology.


Assuntos
Agaricales , Cannabis , Fitoterapia , Preparações de Plantas/uso terapêutico , Dermatopatias/tratamento farmacológico , Pele/patologia , Solanum , Animais , Canabinoides/uso terapêutico , Dermatologia , Dermatomicoses/tratamento farmacológico , Dronabinol/uso terapêutico , Etanolaminas/uso terapêutico , Euphorbia , Fibrose , Humanos , Inflamação/tratamento farmacológico , Ácidos Palmíticos/uso terapêutico , Preparações de Plantas/farmacologia , Podophyllum peltatum , Resveratrol , Ricinus , Envelhecimento da Pele/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Estilbenos/uso terapêutico , Veratrum
8.
ACS Chem Neurosci ; 9(7): 1616-1624, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29708326

RESUMO

Ethanol is a principle ingredient of alcoholic beverages with potential neurotoxicity and genotoxicity, and the ethanol-associated oxidative DNA damage in the central nervous system is well documented. Natural source compounds may offer new options to protect the brain against ethanol-induced genotoxicity. Veratrum maackii Regel is a toxic rangeland plant linked to teratogenicity which is also used in traditional Chinese medicine as "Lilu" and is reported to contain a family of compounds called stilbenes that can have positive biological activity. In this study, nine stilbenes were isolated from the aerial parts of V. maackii Regel, and their structures were identified as cis-mulberroside A (1), resveratrol-4,3'- O-ß-d-diglucopyranoside (2), mulberroside A (3), gentifolin K (4), resveratrol-3,5- O-ß-d-diglucopyranoside (5), oxyresveratrol- 4'- O-ß-d-glucopyranoside (6), oxyresveratrol-3- O-ß-d-glucopyranoside (7), oxyresveratrol (8), and resveratrol (9) using ESI-MS and NMR techniques. The total concentration of extracted compounds 2-9 was 2.04 mg/g, suggesting that V. maackii Regel is a novel viable source of these compounds. In an in vivo comet assay, compounds 1-9 were observed to decrease DNA damage in mouse cerebellum and cerebral cortex caused by acute ethanol administration. Histological observation also revealed decreased brain injury in mice administered with compounds 1-9 after acute ethanol administration. The protective effects of compound 6 were associated with increasing T-SOD and GSH-PX activities and a decrease in NO and MDA concentrations. These findings suggest that these compounds are potent inhibitors of ethanol-induced brain injury possibly via the inhibition of oxidative stress and may be valuable leads for future therapeutic development.


Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Etanol/efeitos adversos , Substâncias Protetoras/farmacologia , Estilbenos/farmacologia , Veratrum , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Masculino , Camundongos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fototerapia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Distribuição Aleatória , Estilbenos/química , Estilbenos/isolamento & purificação
9.
Phytomedicine ; 43: 68-77, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29747756

RESUMO

BACKGROUND: As recorded in the 18 incompatible medicaments of Traditional Chinese Medicine theory, the combined use of Salvia miltiorrhiza bunge (SM) and Veratrum nigrum (VN) could induce toxicity and has been prohibited for thousands of years in China. However, the theory has been validated due to lack of evidence. Previous studies have focused on the chemical constituents that are responsible for the toxicity of the two agents. PURPOSE: This study offers preliminary insight into the pharmacodynamics and mechanism of estrogenic activity responsible for their incompatibility. STUDY DESIGN: We undertook a characterization of the interaction between estrogenic activities of SM and VN using in vivo models of immature and ovariectomized (OVX) mice, and in vitro studies focused on the estrogen receptor (ER) pathway for further mechanism. METHODS: Immature and OVX mice were treated intragastrically with SM at doses of 1.6, 3.2 g/kg, or combine with 0.045 g/kg VN and 0.005 g/kg the ER antagonist ICI182, 780 for elucidating the effects on estrogenic activity in reproductive tissues, E2 secretion, and the ER mechanism. ERα/ß binding experiments and ERα/ß transcriptional activity were performed in order to evaluate the biological action exerted through ERs. RESULTS: VN decreased the estrogenic efficacy of SM in promoting the development of the uterus and vagina in immature mice, and reversing the atrophy of reproductive tissues in OVX mice. VN interfered with the estrogenic efficacy of SM by decreasing the serum estradiol and the upregulation of ERα and ERß expressions in reproductive tissues by treatment with SM. VN antagonized the estrogenic efficacy of SM in promoting the viability of MCF-7 cells and stimulating the binding ability with ERα and ERß, and increasing ERα/ß-estrogen response element (ERE) luciferase activity. CONCLUSIONS: This study provided evidence that the combined use of SM and VN could induce unfavorable effects. VN decreased the estrogenic activity of SM, which might be related to the regulation of estrogen secretion and ERs through the ER-ERE pathway.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Salvia miltiorrhiza , Útero/efeitos dos fármacos , Veratrum , Animais , Antagonismo de Drogas , Medicamentos de Ervas Chinesas/efeitos adversos , Estradiol/sangue , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Medicina Tradicional Chinesa/métodos , Camundongos , Ovariectomia , Receptores Estrogênicos/metabolismo , Útero/patologia , Vagina/efeitos dos fármacos , Vagina/patologia
10.
Clin Toxicol (Phila) ; 56(9): 841-845, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29490507

RESUMO

INTRODUCTION: Steroidal alkaloids are found in plants of the genus Veratrum. Their toxicity manifests as gastrointestinal symptoms followed by a Bezold-Jarisch reflex: hypopnea, hypotension, and bradycardia. Some Veratrum steroidal alkaloids are also teratogens interfering with the hedgehog-2 signaling pathway, which causes cyclopsia and holoprosencephaly. We present a case of accidental poisoning from Veratrum parviflorum mistaken for the edible Allium tricoccum (ramps, wild leek). CASE HISTORY: A 27-year-old man and his 25-year-old wife presented to the emergency department with nausea, vomiting, hypotension, and bradycardia after foraging and ingesting plants that they believed to be a local native species of wild leek. METHODS: We collected and analyzed the implicated fresh plant material and both patients' serum/plasma. We used liquid chromatography-mass spectroscopy and high-resolution electrospray ionization time of flight tandem mass spectrometry to extract and characterize steroidal alkaloids from the foraged plant and patients' serum. RESULTS: Our V. parviflorum samples contained verazine, veratramine, veratridine, and cyclopamine. DISCUSSION: Steroidal alkaloids have been previously isolated from Veratrum viride and Veratrum album and toxicity has been reported mainly from V. album species. CONCLUSION: V. parviflorum toxicity manifests with gastrointestinal and cardiac symptoms. Treatment is symptomatic and supportive as with previous case reports of toxicity with other Veratrum species.


Assuntos
Antieméticos/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Intoxicação por Plantas/tratamento farmacológico , Intoxicação por Plantas/fisiopatologia , Alcaloides de Veratrum/envenenamento , Veratrum/envenenamento , Vômito/tratamento farmacológico , Adulto , Feminino , Gastroenteropatias/etiologia , Georgia , Humanos , Masculino , Resultado do Tratamento , Vômito/etiologia
11.
J Ethnopharmacol ; 220: 177-187, 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29601980

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The pharmacological effect derived from herb-herb interaction is important to constitute the prescription especially in traditional oriental medicine. The relationship of two medicinal herbs is called "couplet medicinals" which is used in pair for the purpose of enhancing the therapeutic effect, reducing the toxic effect or the adverse effect. The "Eighteen Incompatible Medicaments" constitute one of the contents in the incompatibility of traditional oriental drugs in a prescription. Among the "Eighteen Incompatible Medicaments", the roots and rhizomes of Veratrum nigrum (VN), is incompatible with the roots and rhizomes of Panax ginseng (PG). However, definite evidences of adverse effect by these combinations has yet to be reported. MATERIALS AND METHODS: The aim of the present study was to investigate the effects of ethanol extracts of PG, VN, and their combination (P + V) on the metastatic ability of colorectal cancer (CRC) cells using WST assay, flow cytometry, western blot analysis, real-time RT-PCR, immunofluorescence, migration assay, invasion assay, zymography, and an in vivo experiment with a lung-metastasis mouse model. RESULTS: The PG extract decreased cell proliferation by inducing cell cycle arrest and apoptosis of CRC cells. In addition, PG inhibited metastatic abilities of CRC cells including Epithelial-Mesenchymal Transition, migration, and invasion. Additionally, the PG extract suppressed lung metastasis of the CRC cells in the mouse model. However, the P + V extract exhibited weaker anti-proliferative and anti-metastatic effects than PG alone. CONCLUSION: Based on these results, the P + V couplet medicinal attenuates the anti-metastatic effects of PG, both in vitro and in vivo.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Veratrum/química , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/administração & dosagem , Raízes de Plantas , Rizoma
12.
Curr Protein Pept Sci ; 19(3): 302-310, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28059041

RESUMO

Isosteroidal alkaloids are a category of promising bioactive compounds which mostly exist in plants of genus Veratrum and Fritillaria. The pharmacological activities of isosteroidal alkaloids include antihypertensive, antitussive, anti-inflammatory, antithrombosis, among others. Recently, some studies show that this kind of alkaloids exhibited significant antitumor activity. To the best of our knowledge, there is no review focusing on their antitumor activity and mechanism of their antitumor activity. To fill the gap, in this review, we summarized antitumor effects of the isosteroidal alkaloids from genus Veratrum and Fritillaria on different tumors and the mechanisms of their antitumor activity. In conclusion, this kind of alkaloids has extensive antitumor activity, and there are several main mechanisms of their antitumor activity, including the Hedgehog signaling pathway, caspase-3 dependent apoptosis, cell cycle, and autophagy.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Fritillaria/química , Neoplasias/tratamento farmacológico , Veratrum/química , Alcaloides/uso terapêutico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologia , Alcaloides de Veratrum/uso terapêutico
13.
Toxicol Mech Methods ; 27(9): 687-696, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28701067

RESUMO

Veratrum nigrum L. (VN) is a poisonous traditional Chinese medicine herb present since thousands of years in China. Clinical studies have shown that VN has the ability to cause hepatotoxicity, which severely limits its clinical use. The mechanism of its hepatotoxicity has not been fully elucidated. The purpose of this study was to develop and characterize a model of acute and chronic hepatotoxicity induced by Veratrum nigrum L. extract (VNE) to understand the mechanism of liver tissue metabolomics approach using on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOFMS). Mice were administered with VNE in the acute and chronic phases. Histopathologic inspections and biochemistry analysis disclosed severe liver damage after exposure to VNE. A partial least-squares discriminant analysis (PLS-DA) of the metabolomic profiles of rat liver tissues highlighted a number of metabolic disturbances induced by VNE, focusing on purine and pyrimidine metabolism, tryptophan metabolism, phospholipid metabolism, sphingolipid metabolism and fatty acid metabolism. These findings could well explain VNE-induced acute and chronic hepatotoxicity and reveal several potential biomarkers associated with this toxicity. This indicates that UHPLC-Q-TOFMS-based metabolomics approach demonstrated its feasibility and allowed a better understanding of VNE-induced liver toxicity dynamically.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fígado/efeitos dos fármacos , Espectrometria de Massas/métodos , Metabolômica , Extratos Vegetais/toxicidade , Veratrum/química , Animais , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Biomed Chromatogr ; 31(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28544073

RESUMO

The acute cardiotoxicity induced by Veratrum nigrum (VN) is explored by analyzing heart tissue metabolic profiles in mouse models and applying reversed-phase liquid chromatography mass spectrometry and hydrophilic interaction liquid chromatography mass spectrometry that are based on ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. An animal model of acute heart injury was established in mice via intra-gastric administration of VN. Then, electrocardiogram and echocardiograph monitoring of cardiac function and pathological examination were performed on mice in both the control and VN groups, and it was verified that acute heart injury was caused. Meanwhile, comparing the results of the control and VN groups, we detected 36 differential endogenous metabolites of heart tissue, including taurine, riboflavin, purine and lipids, which are related to many possible pathways such as purine metabolism, taurine and hypotaurine metabolism and energy metabolism. Our study provides a scientific approach for evaluating and revealing the mechanisms of VN-induced cardiotoxicity via the metabolomic strategy.


Assuntos
Cardiotoxinas/toxicidade , Cromatografia Líquida de Alta Pressão/métodos , Metaboloma/efeitos dos fármacos , Extratos Vegetais/toxicidade , Veratrum/química , Animais , Cardiotoxicidade/metabolismo , Cardiotoxinas/química , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Espectrometria de Massas/métodos , Redes e Vias Metabólicas , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Extratos Vegetais/química
15.
J Pharm Biomed Anal ; 142: 201-209, 2017 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-28521273

RESUMO

Cyclopamine, an inhibitor of the Hedgehog (Hh) signaling pathway, has been paid much attention in treating a wide variety of tumors. However, isolation and purification of cyclopamine analogs from medicinal plants remain challengeable. We herein proposed an efficient strategy using liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-Q-TOF-MS) and liquid chromatography triple-quadrupole mass spectrometry (LC-QqQ-MS) for rapid screening and targeted isolation of cyclopamine analogs in Fritillaria and Veratrum plants. Firstly, fifteen reference compounds were characterized by LC-Q-TOF-MS and their characteristic fragment ions were summarized. Secondly, according to the characteristic fragment ions at m/z 67.1, 84.1, 109.1 and 114.1, rapid chemical screening of plant extracts was carried out by LC-QqQ-MS using precursor ion scan mode and 69 pre-target compounds were screened out. Thirdly, 24 real target compounds were verified by LC-Q-TOF-MS based on relative abundances (over 20%) of characteristic fragment ions. Fourthly, the targeted isolation of Fritillaria ussuriensis bulb and Veratrum dahuricum rhizome afforded a novel cyclopamine analog namely 15ß-hydroxy-23-isopengbeisine B as well as four known ones, whose structures were determined by nuclear magnetic resonance (NMR) analysis. Additionally, these five analogs were evaluated for the inhibitory activity of Hh signaling pathway in NIH/3T3 cell and cytotoxicity in PANC-1 and HepG2 cells. These results indicated that the proposed strategy was reliable for rapid discovery and targeted isolation of important natural products from chemically complex plant matrices.


Assuntos
Fritillaria , Veratrum , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Espectrometria de Massas em Tandem , Alcaloides de Veratrum
16.
Forensic Sci Int ; 275: 160-166, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28366623

RESUMO

Food poisoning is frequently caused by the accidental ingestion of toxic plants that possess strong morphological similarities to edible plants. False helleborine (Veratrum album) is one of the most common plants involved in such accidents. In cases of poisoning by toxic plants, rapid and accurate identification, usually based on the morphological or chemical analysis of plant parts, is required for appropriate medical treatment or forensic investigation. However, morphological examinations require experience in systematic botany because the samples are fragmentary, and chemical analysis of natural compounds can be difficult. In this study, we developed a TaqMan real-time PCR method using trnH-psbA and trnL-trnF that could be carried out in 30-60min. The lower detection limit was less than 10pg of DNA and the primer sets were specific to V. album and Veratrum stamineum. Mixed samples, cooked samples, and simulated gastric contents were successfully identified, and a multiplex assay of two regions was also possible. These results indicate that the TaqMan real-time PCR analysis is a very effective method to detect small samples of V. album and V. stamineum accurately and rapidly in poisoning cases.


Assuntos
Plantas Tóxicas/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Veratrum/genética , DNA de Plantas/genética , Doenças Transmitidas por Alimentos , Humanos , Reação em Cadeia da Polimerase Multiplex/métodos
17.
Homeopatia Méx ; 86(707): 5-10, mar.-abr. 2017.
Artigo em Espanhol | LILACS, HomeoIndex - Homeopatia | ID: biblio-987093

RESUMO

Este artículo deja en claro que las condiciones neurológicas complejas en los niños deben abordarse desde una perspectiva multidisplinaria en la que la Homeopatía pueda participar positivamente. El trabajo se encuadra en el ámbito clínico y surge de las observaciones que se realizaron en casos paradigmáticos: el de dos niños que respondieron favorablemente al tratamiento homeopático y que fueron seleccionados para esta investigación debido al seguimiento continuo prolongado, y a la claridad de sus necesidades de prescripción. (AU)


This article makes a clear point that the neurological conditions in children should be approached from the multidisciplinary perspective in which Homeopathy can participate positively. This work focuses in the clinical aspect and the observations that were made in the paradigmatic cases: The children responded positively to the homeopathic treatment and were selected for this investigation due to the continuous, prolonged and the clarity of the necessities of prescription.(AU)


Assuntos
Humanos , Masculino , Criança , Homeopatia , Neurologia , Veratrum , Bothrops lanceolatus/uso terapêutico , Mercurius Solubilis/uso terapêutico , Fósforo/uso terapêutico
18.
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
19.
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
20.
Sci Rep ; 6: 25806, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-27194388

RESUMO

Human respiratory syncytial virus (hRSV) is a leading cause of acute lower respiratory tract infection in infants, elderly and immunocompromised individuals. To date, no specific antiviral drug is available to treat or prevent this disease. Here, we report that the Smoothened receptor (Smo) antagonist cyclopamine acts as a potent and selective inhibitor of in vitro and in vivo hRSV replication. Cyclopamine inhibits hRSV through a novel, Smo-independent mechanism. It specifically impairs the function of the hRSV RNA-dependent RNA polymerase complex notably by reducing expression levels of the viral anti-termination factor M2-1. The relevance of these findings is corroborated by the demonstration that a single R151K mutation in M2-1 is sufficient to confer virus resistance to cyclopamine in vitro and that cyclopamine is able to reduce virus titers in a mouse model of hRSV infection. The results of our study open a novel avenue for the development of future therapies against hRSV infection.


Assuntos
Vírus Sincicial Respiratório Humano/fisiologia , Transcrição Genética , Proteínas Virais/metabolismo , Replicação Viral/fisiologia , Alcaloides/farmacologia , Animais , Linhagem Celular , RNA Polimerases Dirigidas por DNA/metabolismo , Modelos Animais de Doenças , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Receptor Smoothened/metabolismo , Transcrição Genética/efeitos dos fármacos , Veratrum/química , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacologia , Alcaloides de Veratrum/uso terapêutico , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
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