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1.
J Chromatogr A ; 1618: 460903, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32035664

RESUMO

Plants of the Digitalis genus contain a cocktail of cardenolides commonly prescribed to treat heart failure. Cardenolides in Digitalis extracts have been conventionally quantified by high-performance liquid chromatography yet the lack of structural information compounded with possible co-eluents renders this method insufficient for analyzing cardenolides in plants. The goal of this work is to structurally characterize cardiac glycosides in fresh-leaf extracts using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) that provides measured accurate mass. Fragmentation of cardenolides is featured by sequential loss of sugar units while the steroid aglycone moieties undergo stepwise elimination of hydroxyl groups, which distinguishes different aglycones. Using a reverse-phase LC column, the sequence of elution follows: diginatigenin→digoxigenin→gitoxigenin→gitaloxigenin→digitoxigenin for cardenolides with the same sugar units but different aglycones. A linear range of 0.8-500 ng ml-1 has been achieved for digoxigenin, ß-acetyldigoxin, and digitoxigenin with limits of detection ranging from 0.09 to 0.45 ngml-1. A total of seventeen cardenolides have been detected with lanatoside A, C, and E as major cardenolides in Digitalis lanata while seven have been found in Digitalis purpurea including purpurea glycoside A, B, and E. Surprisingly, glucodigifucoside in D. lanata and verodoxin and digitoxigenin fucoside in D. purpurea have also been found as major cardenolides. As the first MS/MS-based method developed for analyzing cardenolides in plant extracts, this method serves as a foundation for complete identification and accurate quantification of cardiac glycosides, a necessary step towards understanding the biosynthesis of cardenolide in plants.


Assuntos
Cardenolídeos/análise , Digitalis/química , Espectrometria de Massas em Tandem/métodos , Cromatografia de Fase Reversa , Glicosídeos Digitálicos/análise , Extratos Vegetais/química
5.
Recenti Prog Med ; 110(5): 259-262, 2019 05.
Artigo em Italiano | MEDLINE | ID: mdl-31140460

RESUMO

Vincent Van Gogh and Giovanni Pascoli were artists who shared many aesthetic and biographical affinities. Both were somehow intoxicated by digitalis, the painter literally in a pharmacological sense, the poet symbolically or in a literary sense. In the paper we propose an original theory on how digital affected the last works of the Dutch painter and in particular the portrait of doctor Gachet, which differs from the previous theories, that attribute the chromatic style of Van Gogh to the xanthopsia caused by digitalis overdose. The Italian poet dedicated a short poem to the Foxglove, inspired by the popular wisdom that centuries ago already recognized the poisonous power of Foxglove.


Assuntos
Arte/história , Digitalis/envenenamento , Poesia como Assunto/história , Pessoas Famosas , História do Século XIX , História do Século XX , Humanos
6.
Fitoterapia ; 135: 90-98, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31014930

RESUMO

The phytochemical studies on the aerial parts of Digitalis davisiana Heywood led to the isolation of three undescribed phenylethanoid glycosides named as digidavisoside A (5), digidavisoside B (7), and davisoside (8), along with 9 known compounds, ferruginoside B (1), isolugrandoside (2), lugrandoside (3), maxoside (4), 3″″-O-methylmaxoside (6), trans-lamiuside E (9), digiciliside B (10), p-hydroxyacetophenone (11), and chrysoeriol (12). For the first time compound 11 was reported for Digitalis genus. The chemotaxonomical significance of these compounds in Plantaginaceae family was evaluated and 3'-O-glucosyl substituted phenylethanoid glycosides 4-8 and 10 were found to be chemotaxonomically important for the family. Cytotoxic activity of the aqueous fraction of the methanolic extract was also tested against HEp-2 (human larynx epidermoid carcinoma) and HepG2 (human hepatocellular carcinoma) cancer cell lines. The aqueous fraction showed stronger cytotoxicity on HEp-2 cells than on HepG2. Therefore, the cytotoxic activity of 1-4, 6, 7 and 9 were tested against HEp-2 and L929 (mouse fibroblast cell) cell lines. Other isolated compounds could not be tested due to their insufficient amount. The results were evaluated in the point of structure-activity relationships. IC50 values against HEp-2 cells were established in a range of 71.9-220 µM. Maxoside (4), isolugrandoside (2) and lugrandoside (3) showed higher cytotoxicity against HEp-2 cell line than other isolated compounds.


Assuntos
Digitalis/química , Glicosídeos/farmacologia , Álcool Feniletílico/farmacologia , Compostos Fitoquímicos/farmacologia , Animais , Linhagem Celular Tumoral , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Camundongos , Estrutura Molecular , Álcool Feniletílico/química , Álcool Feniletílico/isolamento & purificação , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Componentes Aéreos da Planta/química , Relação Estrutura-Atividade
8.
Fitoterapia ; 134: 73-80, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30735707

RESUMO

Phytochemical investigation of the aerial parts of Digitalis grandiflora Miller (Plantaginaceae) led to the isolation of an undescribed cardenolide type glycoside digigrandifloroside (1) along with five known compounds, rengyoside A (2), rengyoside B (3), cleroindicin A (4), salidroside (5), and cornoside (6), from its aqueous fraction of methanolic extract. Structures of the isolated compounds were determined by means of spectroscopic techniques. 1-6 were isolated for the first time from D. grandiflora. 2 and 3 are being reported for the first time from Digitalis genus and Plantaginaceae family with this study. This is the second report for occurrence of 4 from a Digitalis species. Cytotoxic activity of the aqueous fraction was also tested against HEp-2 (Human larynx epidermoid carcinoma) and HepG2 (Human hepatocellular carcinoma) cancer cell lines and L929 (Mouse fibroblast cell) non-cancerous cell line. Aqueous fraction showed stronger cytotoxicity on HEp-2 cells than HepG2. Therefore, the cytotoxic activity of 1, 2, 4, and 6 were tested against HEp-2 and L929 cell lines. 3 and 5 couldn't be tested due to their insufficient amount. 1 showed the highest cytotoxicity against HEp-2 cells with IC50 value 10.1 µM when compared with the positive control, etoposide and 2-6 (IC50 of etoposide; 39.5 µM).


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cardenolídeos/farmacologia , Digitalis/química , Glicosídeos/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Cardenolídeos/isolamento & purificação , Linhagem Celular Tumoral , Glicosídeos/isolamento & purificação , Humanos , Camundongos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química , Metabolismo Secundário , Turquia
9.
Sci Rep ; 8(1): 18009, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30573772

RESUMO

In this report, we have investigated the influence of different light qualities on Digitalis purpurea under a controlled environment. For this purpose, red (R), blue (B), fluorescent lamp (FL, control), along with combined red and blue (R:B) LEDs were used. Interestingly, the plant growth parameters such as number of leaf, longest root, width of leaf, width of stomata, width of trichome, leaf area, leaf or root fresh weight (FW), weight (DW) as well as length of trichome were maximum under R:B (8:2), and significantly larger than control plants. The stomatal conductance or anthocyanin was maximum under B LED than those under FL, however the photosynthesis rate was greater under FL. RuBisCO activity was maximum under R:B (1:1) LEDs while the quantity of the UV absorbing substances was highest under R LED than under FL. The maximum amount of cardenolides were obtained from leaf tissue under R:B (2:8) LED than those under FL. The R:B LEDs light was suitable for Digitalis plant growth, development, micro- and macro-elements, as well as cardenolides accumulation in the plant factory system. The adaptation of the growth strategy developed in this study would be useful for the production of optimized secondary metabolites in Digitalis spp.


Assuntos
Agricultura/métodos , Cardenolídeos/metabolismo , Digitalis , Ambiente Controlado , Luz , Desenvolvimento Vegetal/efeitos da radiação , Biomassa , Digitalis/crescimento & desenvolvimento , Digitalis/metabolismo , Digitalis/efeitos da radiação , Fotossíntese
10.
Cell Mol Biol (Noisy-le-grand) ; 64(14): 89-95, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30511627

RESUMO

Digitalis nervosa is an important medicinal plant species belonging to the family of Scrophulariaceae that has the potential to be used for heart failure. 3ß-hydroxysteroid dehydrogenase (3ß-HSD) is a key gene in the biosynthesis of cardenolides for making digitalis effective compounds, hence identification of this gene is important for genetic engineering purposes towards increasing the yield of cardiac glycosides. In addition, mRNA-like non-coding RNAs (mlncRNAs), a class of long non coding RNAs, play key roles in various biological processes and may affect cardenolides pathway in digitalis plants.  In the present work, full sequence of 3ß-HSD was isolated from Digitalis nervosa. Gene expression patterns of 3ß-HSD along with three mlncRNAs including mlncRNA23, mlncRNA28 and mlncRNA30 were studied and the results indicated that they are differentially expressed in different tissues including roots, stems and leaves, with the highest expression levels in leaves.  Moreover, the transcript levels of these genes affected by the cold and drought stresses. The results obtained from the present study is important in order to understand the potential role of mlncRNAs in digitalis plants, especially in response to abiotic stresses.


Assuntos
17-Hidroxiesteroide Desidrogenases/genética , Digitalis/enzimologia , Digitalis/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , RNA Longo não Codificante/genética , Estresse Fisiológico/genética , 17-Hidroxiesteroide Desidrogenases/química , 17-Hidroxiesteroide Desidrogenases/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Vias Biossintéticas/genética , Cardenolídeos/química , Cardenolídeos/metabolismo , Temperatura Baixa , Digitalis/fisiologia , Secas , Especificidade de Órgãos/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
Phytochemistry ; 156: 9-19, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30172078

RESUMO

PRISEs (progesterone 5ß-reductase and/or iridoid synthase-like 1,4-enone reductases) are involved in cardenolide and iridoid biosynthesis. We here investigated a PRISE (rAtSt5ßR) from Arabidopsis thaliana, a plant producing neither cardenolides nor iridoids. The structure of rAtSt5ßR was elucidated with X-ray crystallography and compared to the known structures of PRISEs from Catharanthus roseus (rCrISY) and Digitalis lanata (rDlP5ßR). The three enzymes show a high degree of sequence and structure conservation in the active site. Amino acids previously considered to allow discrimination between progesterone 5ß-reductase and iridoid synthase were interchanged among rAtSt5ßR, rCrISY and rDlP5ßR applying site-directed mutagenesis. Structural homologous substitutions had different effects, and changes in progesterone 5ß-reductase and iridoid synthase activity were not correlated in all cases. Our results help to explain fortuitous emergence of metabolic pathways and product accumulation. The fact that PRISEs are found ubiquitously in spermatophytes insinuates that PRISEs might have a more general function in plant metabolism such as, for example, the detoxification of reactive carbonyl species.


Assuntos
Catharanthus/enzimologia , Digitalis/enzimologia , Oxirredutases/metabolismo , Biocatálise , Catharanthus/metabolismo , Digitalis/metabolismo , Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Estrutura Molecular
12.
Am J Cardiovasc Drugs ; 18(6): 427-440, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30066080

RESUMO

The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.


Assuntos
Cardiotônicos/uso terapêutico , Glicosídeos Digitálicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Fatores Etários , Fibrilação Atrial/tratamento farmacológico , Peso Corporal , Cardiotônicos/efeitos adversos , Cardiotônicos/farmacologia , Digitalis , Glicosídeos Digitálicos/efeitos adversos , Glicosídeos Digitálicos/farmacologia , Digoxina/farmacologia , Digoxina/uso terapêutico , Interações Medicamentosas , Monitoramento de Medicamentos , Humanos , Metanálise como Assunto , Neoplasias/tratamento farmacológico , Estudos Observacionais como Assunto , Ouabaína/farmacologia , Ouabaína/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Fatores Sexuais , Volume Sistólico
13.
Biomed Pharmacother ; 105: 533-539, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29885637

RESUMO

BACKGROUND: Toxic effects of digoxin may occur with normal therapeutic serum level. However, the underlying mechanisms are not fully understood. Nuclear factor kappa-B (NF-kB) is an important transcription factor in most organ systems and is often implicated in the harmful effects of cardiac injury. NF-kB promotes inflammatory responses, mediates adverse cardiac remodeling and has a function correlation with calcium. The voltage-gated L-type calcium channel CaV1.2 mediates the influx of Ca+2 into the cell in response to membrane depolarization. Our aim was to characterize the role of NF-kB during digoxin toxicity and to assess its correlation with Cav 1.2 in healthy mice in vivo. METHODS: To address these questions, digoxin was administered in doses of 0.1, 1 or 5 mg/kg orally daily for seven days to the animals. Serum digoxin, serum calcium, atrial and ventricular calcium levels were measured. We, also, looked for NF-kB and CaV1.2 channel expression in cardiac muscle of mice. RESULTS: Digoxin at a dose of 0.1 mg/kg did not enhance serum, atrial, and ventricular Ca+2 levels, but were increased when digoxin dose of 1 and 5 mg/kg were administered. Histologically, myocardial necrosis and cellular infiltration on day 7 were significantly more severe in the 5 mg/kg/day digoxin group. Immunohistochemical studies showed more expression of both NF-kB and CaV1.2 in 1 and 5 mg/kg/day digoxin groups. CONCLUSIONS: These data suggest that NF-kB may be responsible for digoxin toxicity, at least partially via modulation of CaV1.2 and intracellular calcium homeostasis in the myocardium.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Digitalis/toxicidade , Digoxina/toxicidade , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Animais , Cálcio/sangue , Digoxina/administração & dosagem , Digoxina/sangue , Eletrocardiografia , Átrios do Coração/patologia , Ventrículos do Coração/patologia , Masculino , Camundongos , Fator de Transcrição RelA/metabolismo
14.
Kardiologiia ; (S5): 13-19, 2018.
Artigo em Russo | MEDLINE | ID: mdl-29894672

RESUMO

In recent years there has been a marked decrease in cardiac glycosides use in patients with heart failure in sinus rhythm and atrial fibrillation. The results of published studies contradict each other. Some of them doubt the favorable effect of digoxin in patients with heart failure; others refute the increase in the lethality and frequency of hospitalizations associated with the use of digoxin. In this regard, we found it important to analyze these reports impartially and reflect modern views on the mechanisms of cardiac glycosides, the pharmacokinetics and the possibility of optimizing digitalis therapy in cardiac practice.


Assuntos
Fibrilação Atrial , Digitalis , Insuficiência Cardíaca , Glicosídeos Digitálicos , Digoxina , Humanos
15.
J Electrocardiol ; 51(3): 450-451, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29477502

RESUMO

This report describes a digitalis-induced regular fascicular ventricular tachycardia characterized by marked QRS alternans a manifestation not usually associated with this arrhythmia. The striking alternation of QRS configuration suggested alternating ventricular activation from either a single focus with two exits in distal branches of the left anterior fascicle or 2 different foci localized in the Purkinje-myocardial network of the left anterior fascicle.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Fascículo Atrioventricular/fisiopatologia , Digitalis/envenenamento , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/fisiopatologia , Antiarrítmicos/uso terapêutico , Quimioterapia Combinada , Eletrocardiografia , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Lidocaína/uso terapêutico , Pessoa de Meia-Idade , Taquicardia Ventricular/tratamento farmacológico
18.
J Nucl Med ; 59(5): 780-786, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29242405

RESUMO

Anaplastic thyroid cancer (ATC) is a rare malignancy that accounts for 1%-2% of all thyroid cancers. ATC is one of the most aggressive human cancers, with rapid growth, tumor invasion, and development of distant metastases. The median survival is only 5 mo, and the 1-y survival is less than 20%. Moreover, as a result of severe dedifferentiation, including the loss of human sodium iodide symporter (hNIS) expression, radioactive iodide (RAI) therapy is ineffective. Recently, we have demonstrated beneficial effects of autophagy-activating digitalislike compounds (DLCs) on redifferentiation and concomitant restoration of iodide uptake in RAI-refractory papillary and follicular thyroid cancer cell lines. In the current study, the effects of DLCs on differentiation and proliferation of ATC cell lines were investigated. Methods: Autophagy activity was assessed in ATC patient tissues by immunofluorescent staining for the autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3). In addition, the effect of autophagy-activating DLCs on the proliferation, gene expression profile, and iodide uptake capacity of ATC cell lines was studied. Results: Diminished autophagy activity was observed in ATC tissues, and in vitro treatment of ATC cell lines with DLCs robustly restored hNIS and thyroglobulin expression and iodide uptake capacity. In addition, proliferation was strongly reduced by induction of cell cycle arrest and, to some extent, cell death. Mechanistically, reactivation of functional hNIS expression could be attributed to activation of the transcription factors activating transcription factor 3 and protooncogene c-fosConclusion: DLCs could represent a promising adjunctive therapy for restoring iodide avidity within the full spectrum from RAI-refractory dedifferentiated to ATC.


Assuntos
Digitalis/química , Iodetos/metabolismo , Simportadores/metabolismo , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/metabolismo , Fator 3 Ativador da Transcrição/metabolismo , Adenocarcinoma Folicular/tratamento farmacológico , Adenocarcinoma Folicular/metabolismo , Autofagia , Ciclo Celular , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Radioisótopos do Iodo , Microscopia de Fluorescência , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-fos/metabolismo , Tireoglobulina/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo
19.
Curr Pharm Des ; 23(34): 5104-5114, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28847302

RESUMO

The genus Digitalis L. containing species, commonly known as the "foxglove", is the main source of cardenolides, which have various pharmacological properties effective against certain pathological conditions including myocardial infarction, arterial hypertension, cardiac dysfunction, angina, and hypertrophy. Togehter with a prime effect of controlling the heart rhythm, many workers demonstrated that lanatoside C and some other cardiac glycosides are effective in several cancer treatments such as prostate and breast cancers. Due to digoxigenin derivatives of cardenolides, which are mainly used for medicinal purposes, such as digoxigenin, D. lanata as a main source is of great interest for commercial scale production of cardenolides in Europe. Phytochemical studies on cardenolides, naturally occurring plant secondary metabolites, have mainly focused on the species of the genus Digitalis L., as the members of this family have a high level and diverse content of cardenolides. During the last few decades, plant tissue culture techniques have been optimised for many plant species including Digitalis, however, the production capacity of cardenolides somehow failed to reach a commercially desired extent. In this review paper, the genus Digitalis is evaluated in terms of its main botanical and physiological features, traditional uses, molecular genetics and metabolomics, cellular mechanism of action, medicinal uses, clinical pharmacology, drug interactions, therapy in the management of cardiovascular disorders, potential utility of therapy in extracardiac conditions, and toxicity.


Assuntos
Cardenolídeos/uso terapêutico , Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Digitalis , Extratos Vegetais/uso terapêutico , Animais , Cardenolídeos/química , Cardenolídeos/isolamento & purificação , Cardiotônicos/química , Cardiotônicos/isolamento & purificação , Doenças Cardiovasculares/fisiopatologia , Digitalis/química , Humanos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
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