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1.
Plant Cell Rep ; 40(9): 1631-1646, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34146141

RESUMO

KEY MESSAGE: Studying RNAi-mediated DlP5ßR1 and DlP5ßR2 knockdown shoot culture lines of Digitalis lanata, we here provide direct evidence for the participation of PRISEs (progesterone 5ß-reductase/iridoid synthase-like enzymes) in 5ß-cardenolide formation. Progesterone 5ß-reductases (P5ßR) are assumed to catalyze the reduction of progesterone to 5ß-pregnane-3,20-dione, which is a crucial step in the biosynthesis of the 5ß-cardenolides. P5ßRs are encoded by VEP1-like genes occurring ubiquitously in embryophytes. P5ßRs are substrate-promiscuous enone-1,4-reductases recently termed PRISEs (progesterone 5ß-reductase/iridoid synthase-like enzymes). Two PRISE genes, termed DlP5ßR1 (AY585867.1) and DlP5ßR2 (HM210089.1) were isolated from Digitalis lanata. To give experimental evidence for the participation of PRISEs in 5ß-cardenolide formation, we here established several RNAi-mediated DlP5ßR1 and DlP5ßR2 knockdown shoot culture lines of D. lanata. Cardenolide contents were lower in D. lanata P5ßR-RNAi lines than in wild-type shoots. We considered that the gene knockdowns may have had pleiotropic effects such as an increase in glutathione (GSH) which is known to inhibit cardenolide formation. GSH levels and expression of glutathione reductase (GR) were measured. Both were higher in the Dl P5ßR-RNAi lines than in the wild-type shoots. Cardenolide biosynthesis was restored by buthionine sulfoximine (BSO) treatment in Dl P5ßR2-RNAi lines but not in Dl P5ßR1-RNAi lines. Since progesterone is a precursor of cardenolides but can also act as a reactive electrophile species (RES), we here discriminated between these by comparing the effects of progesterone and methyl vinyl ketone, a small RES but not a precursor of cardenolides. To the best of our knowledge, we here demonstrated for the first time that P5ßR1 is involved in cardenolide formation. We also provide further evidence that PRISEs are also important for plants dealing with stress by detoxifying reactive electrophile species (RES).


Assuntos
Cardenolídeos/metabolismo , Digitalis/genética , Digitalis/metabolismo , Oxirredutases/genética , Proteínas de Plantas/genética , Butanonas/farmacologia , Butionina Sulfoximina/farmacologia , Digitalis/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas , Técnicas de Silenciamento de Genes , Glutationa/farmacologia , Oxirredutases/metabolismo , Proteínas de Plantas/metabolismo , Brotos de Planta/genética , Plantas Geneticamente Modificadas , Progesterona/farmacologia , Interferência de RNA , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
2.
Clin Ther ; 43(5): 852-858.e2, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33888353

RESUMO

PURPOSE: Dronedarone may increase digoxin plasma levels through inhibition of P-glycoprotein. Using real-world data, we evaluated the risk of digitalis intoxication in concomitant users of dronedarone and digoxin compared digoxin-alone users. METHODS: We used the Clinformatics DataMart, a US claims database, to identify adult patients with atrial fibrillation (AF) or atrial flutter (AFL) who concomitantly used dronedarone and digoxin and those who used digoxin alone between July 2009 and March 2016. Digitalis intoxication during follow-up until March 2016 was ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Adjusted hazard ratios (HR) for digitalis intoxication in concomitant users versus users of digoxin alone were estimated, controlling for age, sex, cohort entry year, number of medical encounters for AF or AFL, history of congestive heart failure, diabetes, hypertension, stroke, myocardial infarction, renal failure, use of drugs interacting with digoxin, and digoxin dose. FINDINGS: Overall, 524 concomitant users and 32,459 users of digoxin alone were identified, among which 3 and 301 events of digitalis intoxication occurred during follow-up, respectively. Incidence rates were 17.25 and 9.17 cases per 1000 person-years, respectively. The adjusted HR for digitalis intoxication in concomitant users versus users of digoxin alone was 1.56 (95% CI, 0.50-4.88; P = 0.45). When digitalis intoxication was defined by ICD-9-CM and ICD-10-CM codes accompanied by laboratory testing for digoxin/digitoxin or hospitalization within 30 days, no events occurred in the concomitant users and 40 events occurred in the users of digoxin alone (incidence rate of 1.22 cases per 1000 person-years). IMPLICATIONS: Concomitant use of dronedarone and digoxin was uncommon in this study, and no significant increase in the risk of digitalis intoxication with concomitant use was found.


Assuntos
Fibrilação Atrial , Flutter Atrial , Digitalis , Adulto , Fibrilação Atrial/tratamento farmacológico , Digoxina/efeitos adversos , Dronedarona , Humanos
3.
Parasite ; 28: 38, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33851916

RESUMO

Current treatments of visceral leishmaniasis face limitations due to drug side effects and/or high cost, along with the emergence of parasite resistance. Novel and low-cost antileishmanial agents are therefore required. We report herein the antileishmanial activity of ß-acetyl-digitoxin (b-AD), a cardenolide isolated from Digitalis lanata leaves, assayed in vitro and in vivo against Leishmania infantum. Results showed direct action of b-AD against parasites, as well as efficacy for the treatment of Leishmania-infected macrophages. In vivo experiments using b-AD-containing Pluronic® F127 polymeric micelles (b-AD/Mic) to treat L. infantum-infected mice showed that this composition reduced the parasite load in distinct organs in more significant levels. It also induced the development of anti-parasite Th1-type immunity, attested by high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and specific IgG2a antibodies, in addition to low IL-4 and IL-10 contents, along with higher IFN-γ-producing CD4+ and CD8+ T-cell frequency. Furthermore, low toxicity was found in the organs of the treated animals. Comparing the therapeutic effect between the treatments, b-AD/Mic was the most effective in protecting animals against infection, when compared to the other groups including miltefosine used as a drug control. Data found 15 days after treatment were similar to those obtained one day post-therapy. In conclusion, the results obtained suggest that b-AD/Mic is a promising antileishmanial agent and deserves further studies to investigate its potential to treat visceral leishmaniasis.


Assuntos
Antiprotozoários , Digitalis , Leishmania infantum , Leishmaniose Visceral , Animais , Antiprotozoários/uso terapêutico , Cardenolídeos/uso terapêutico , Digitoxina/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C
4.
Phytochemistry ; 187: 112710, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33930670

RESUMO

Three putative 21-hydroxypregnane 21-O-malonyltransferases (21MaT) from Digitalis lanata were partially purified. Two of them were supposed to be BAHD-type enzymes. We were unable to purify them in quantities necessary for reliable sequencing. We identified two genes in A. thaliana coding for substrate-promiscuous BAHD-type phenolic glucoside malonyltransferases (AtPMaT1, AtPMaT2) and docked various 21-hydroxypregnanes into the substrate-binding site of a homology model built on the BAHD template 2XR7 (NtMaT1 from N. tabacum). Recombinant forms of Atpmat1 and Atpmat2 were expressed in E. coli and the recombinant enzymes characterized with regard to their substrate preferences. They were shown to malonylate various 21-hydroxypregnanes. The Atpmat1 sequence was used to identify candidate genes in Digitalis lanata (Dlmat1 to Dlmat4). Dlmat1 and Dlmat2 were also expressed in E. coli and shown to possess 21-hydroxypregnane 21-O-malonyltransferase activity.


Assuntos
Arabidopsis , Digitalis , Arabidopsis/genética , Cardenolídeos , Escherichia coli/genética , Glucosídeos
5.
Pest Manag Sci ; 77(6): 2690-2696, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33638225

RESUMO

BACKGROUND: Larvae of many hoverfly species prey upon aphids, whereas the adults, by relying on nectar and pollen, contribute to the pollination of many plant species. Despite their great potential for pest control and pollination, important gaps still exist regarding the efficacy of hoverflies in regulating infestations of major aphid pests in augmentative biological control programs. Here, we tested the potential of the commercially available hoverflies Eupeodes corollae and Sphaerophoria rueppellii to regulate populations of the foxglove aphid Aulacorthum solani in sweet pepper. RESULTS: In a semi-field experiment, aphid numbers were 93.2% and 78.4% lower in the E. corollae and S. rueppellii treatments, respectively, compared to the control. Fruit yield was increased by 390% and 361% and seed set by 395% and 399% for E. corollae and S. rueppellii. In a separate laboratory trial, we found that under conditions of limited prey, hoverfly larvae did not complete development, but that larvae of S. rueppellii survived significantly longer than larvae of E. corollae. CONCLUSION: We have shown for the first time that E. corollae and S. rueppellii can reduce infestations of foxglove aphid in sweet pepper. The limited amount of prey, related to the small size of the A. solani colonies, means that hoverfly larvae were often not able to complete development. In practice, repeated releases of hoverflies, possibly in combination with other natural enemies, might be used to achieve effective suppression of A. solani infestations. © 2021 Society of Chemical Industry.


Assuntos
Afídeos , Capsicum , Digitalis , Animais , Frutas , Controle Biológico de Vetores , Sementes
6.
Mol Biol Rep ; 48(1): 127-137, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33403559

RESUMO

There is an increasing demand for elucidating the biosynthetic pathway of medicinal plants, which are capable of producing several metabolites with great potentials for industrial drug production. Digitalis species are important medicinal plants for the production of cardenolide compounds. Advancement on culture techniques is strictly related to our understanding of the genomic background of species. There are a limited number of genomic studies on Digitalis species. The goal of this study is to contribute to the genomic data of Digitalis ferruginea subsp. schischkinii by presenting transcriptome annotation. Digitalis ferruginea subsp. schischkinii has a limited distribution in Turkey and Transcaucasia, and has a high level of lanatoside C, an important cardenolide. In the study, we sequenced the cDNA library prepared from RNA pools of D. ferruginea subsp. schischkinii tissues treated with various stress conditions. Comprehensive bioinformatics approaches were used for de novo assembly and functional annotation of D. ferruginea subsp. schischkinii transcriptome sequence data along with TF families predictions and phylogenetic analysis. In the study, 58,369 unigenes were predicted and unigenes were annotated by analyzing the sequence data in the non-redundant (NR) protein database, the non-redundant nucleotide (NT) database, Gene Orthology (GO), EuKaryotic Orthologous Groups (KOG), Kyoto Encyclopedia of Genes and Genomes (KEGG), SwissProt, and InterPro databases. This study is the first transcriptome data for D. ferruginea subsp. schischkinii.


Assuntos
Vias Biossintéticas/genética , Digitalis/genética , Repetições de Microssatélites/genética , Transcriptoma/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Anotação de Sequência Molecular , Filogenia , Plantas Medicinais/química
9.
Ned Tijdschr Geneeskd ; 1642020 11 12.
Artigo em Holandês | MEDLINE | ID: mdl-33331728

RESUMO

BACKGROUND: At a time when self-sufficiency and health are becoming increasingly important in society, the chances of intoxications with wild plants are increasing. Foxglove contains poisonous cardiac glycosides such as digoxin, digitoxin and gitoxin. The levels vary greatly and depend on the season and the location of the plants. The "non-digoxin" cardiac glycosides show a limited cross-reaction with the digoxin assay. This means that a low or therapeutic digoxin level does not rule out a severe foxglove intoxication. Due to the long half-life of the different cardiac glycosides, toxic symptoms can be persistent. CASE DESCRIPTION: A 43-year-old woman arrived at the Emergency Department with persistent vomiting and specific ECG-abnormalities. The day before, she drunk a smoothie made from wild plants picked in the woods. Patient appeared to have mistaken foxglove for common sorrel. CONCLUSION: In case of persistent gastrointestinal complaints with specific ECG abnormalities after ingestion of plant material, clinicians should be aware of a foxglove intoxication.


Assuntos
Digitalis/envenenamento , Doenças Transmitidas por Alimentos/etiologia , Vômito/etiologia , Adulto , Feminino , Humanos
10.
J Pharm Biomed Anal ; 191: 113614, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32980793

RESUMO

The present study outlines the phenolic composition and pharmacological properties of different extracts of Digitalis cariensis Boiss. ex Jaub. & Spach root and aerial parts. The metabolic profiles of the studied extracts were characterized by UHPLC-MS. The in vitro antioxidant and enzyme (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, α-amylase, and α-glucosidase) inhibitory potential of the extracts were determined. Bioinformatics and docking investigations were also conducted to support the enzyme inhibition test and predict putative targets for potential pharmacological applications. Overall, the methanolic extract followed by the water extract of the D. cariensis root were found to be superior source of antioxidant compounds except for metal chelating ability, in which the water extract of the root (26.34 ± 1.54 mg EDTAE/g) and aerial parts (16.47 ± 0.88 mg EDTAE/g) have showed the highest activity. The tested extracts were potent against AChE (9.11 ± 0.27-9.79 ± 0.28 mg GEs/g extract), α-amylase (0.12 ± 0.01- 0.50 ± 0.01 mmol ACEs/g extract) and α-glucosidase (0.28 ± 0.01-17.29 ± 0.24 mmol ACEs/ g extract). Notable activity against tyrosinase was displayed by the methanolic extracts (Root-MeOH: 123.71 ± 2.70 and aerial parts - MeOH: 137.96 ± 1.07 mg KAE/g extract), while none of the extracts were potent against BChE. According to docking investigations, the observed anti-tyrosinase effect could be related, at least partially, to the presence of luteolin, rosmarinic acid and kaempferol in the extracts. Results amassed herein is the first report on the biological attributes of D. cariensis, which validate the pharmacological uses of this plant.


Assuntos
Antioxidantes , Digitalis , Antioxidantes/farmacologia , Monofenol Mono-Oxigenase , Fenóis/farmacologia , Extratos Vegetais/farmacologia
11.
Am J Cardiol ; 136: 164-165, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32941822
12.
Cardiol Young ; 30(12): 1856-1865, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32959746

RESUMO

Vincent van Gogh (1853-1890) is one of the most famous artists in the world. During his 10-year career as an artist, he created more than 850 paintings. These works of art are now displayed in museums around the globe. It is therefore even more surprising that van Gogh sold just one painting during his lifetime. Van Gogh is also well-known for his mental illness. In 1888, at the age of 35, he famously sliced off his left ear. This was followed by multiple mental collapses in early 1889, leading to his admission to a mental hospital. Despite living in the asylum, van Gogh continued to paint and created some of his most beautiful works of art during the year at Saint-Rémy. Tragically, he committed suicide in 1890 at the age of 37. Over the 130 years since his death, there has been much speculation about the underlying illness of Vincent van Gogh. Many of his contemporary physicians felt that he had a form of epilepsy as the cause of his sudden "attacks". By the last quarter of the 19th century, science and medicine were moving rapidly forward, and there were many medical conditions that had effective treatments. One example is the use of digoxin for the treatment of heart failure, and another is the discovery of potassium bromide for seizures. This paper provides an overview of van Gogh's mental illness, the treatments that were offered by his contemporaneous physicians, and the role that these factors may have influenced his paintings.


Assuntos
Digitalis , Pessoas Famosas , Transtornos Mentais , Pinturas , Médicos , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Países Baixos
13.
ESC Heart Fail ; 7(5): 2082-2092, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32608191

RESUMO

AIMS: Amiodarone and digitalis are frequently used drugs in patients with heart failure. Both have separately been linked to reduced post-transplant survival, but their combined impact on mortality after HTX remains uncertain. This study investigated the effects of combined amiodarone and digitalis use before HTX on post-transplant outcomes. METHODS AND RESULTS: This registry study analysed 600 patients receiving HTX at Heidelberg Heart Center between 1989 and 2016. Patients were stratified by amiodarone and digitalis use before HTX. Analysis included patient characteristics, medication, echocardiographic features, heart rates, permanent pacemaker implantation, atrial fibrillation, and post-transplant survival including causes of death. One hundred eighteen patients received amiodarone before HTX (19.7%), hereof 67 patients with digitalis (56.8%) and 51 patients without digitalis before HTX (43.2%). Patients with and without amiodarone before HTX showed a similar 1 year post-transplant survival (72.0% vs. 78.4%, P = 0.11), but patients with combined amiodarone and digitalis before HTX had a worse 1 year post-transplant survival (64.2%, P = 0.01), along with a higher percentage of death due to transplant failure (P = 0.03). Echocardiographic analysis of these patients showed a higher percentage of an enlarged right ventricle (P = 0.02), left atrium (P = 0.02), left ventricle (P = 0.03), and a higher rate of reduced left ventricular ejection fraction (P = 0.03). Multivariate analysis indicated combined amiodarone and digitalis use before HTX as a significant risk factor for 1 year mortality after HTX (hazard ratio: 1.69; 95% confidence interval: 1.02-2.77; P = 0.04). CONCLUSIONS: Combined pre-transplant amiodarone and digitalis therapy is associated with increased post-transplant mortality.


Assuntos
Amiodarona , Digitalis , Transplante de Coração , Humanos , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda
14.
J Biochem Mol Toxicol ; 34(5): e22462, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045083

RESUMO

Heart failure (HF) is a medical condition inability of the heart to pump sufficient blood to meet the metabolic demand of the body to take place. The number of hospitalized patients with cardiovascular diseases is estimated to be more than 1 million each year, of which 80% to 90% of patients ultimately progress to decompensated HF. Digitalis glycosides exert modest inotropic actions when administered to patients with decompensated HF. Although its efficacy in patients with HF and atrial fibrillation is clear, its value in patients with HF and sinus rhythm has often been questioned. A series of recent studies have cast serious doubt on the benefit of digoxin when added to contemporary HF treatment. We are hypothesizing the role and mechanism of exosome and its biological constituents responsible for worsening the disease state and mortality in decompensated HF patients on digitalis.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Cardiotônicos/uso terapêutico , Digitalis/química , Digoxina/uso terapêutico , Exossomos/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Antiarrítmicos/farmacologia , Cardiotônicos/farmacologia , Digoxina/farmacologia , Humanos , Extratos Vegetais/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
15.
Antonie Van Leeuwenhoek ; 113(6): 773-778, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32086682

RESUMO

Three strains originating from insect frass in South Africa, yellow foxglove in Hungary and soil in France, were characterised phenotypically and by sequencing of the D1/D2 domain of the large subunit and the ITS1-5.8S-ITS2 (ITS)-region of the rRNA gene. The strains have identical D1/D2 domain sequences and only one strain shows a 1 bp indel in a 9 bp homopolymer A/T repeat within the ITS-region. Based on sequence analysis Hyphopichia burtonii is the closest related species. The investigated strains differ from the type strain of H. burtonii by 1.9% (9 substitutions and an indel) in the D1/D2 domain and by 23 substitutions and 21-22 indels in the ITS-region. Since the sequence variability is very low among the three strains and the sequence divergence with the closely related H. burtonii exceeds the level generally encountered between species we propose the new species Hyphopichia lachancei f.a., sp. nov. to accommodate the three novel strains. From H. burtonii the new species can be distinguished phenotypically by its inability to ferment cellobiose and by the formation of endospores (Holotype: CBS 5999T; Isotype: NCAIM Y.02228T; MycoBank no.: MB833616).


Assuntos
Saccharomycetales , Animais , Celobiose/metabolismo , DNA Fúngico , DNA Ribossômico , DNA Espaçador Ribossômico/genética , Digitalis/microbiologia , Fezes/microbiologia , França , Hungria , Insetos/microbiologia , Estágios do Ciclo de Vida , Fenótipo , Filogenia , Saccharomycetales/classificação , Saccharomycetales/genética , Saccharomycetales/isolamento & purificação , Saccharomycetales/metabolismo , Microbiologia do Solo , África do Sul
16.
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
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