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1.
Arch Virol ; 165(6): 1385-1396, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32346764

RESUMO

Human herpesviruses are among the most prevalent pathogens worldwide and have become an important public health issue. Recurrent infections and the emergence of resistant viral strains reinforce the need of searching new drugs to treat herpes virus infections. Cardiac glycosides are used clinically to treat cardiovascular disturbances, such as congestive heart failure and atrial arrhythmias. In recent years, they have sparked new interest in their potential anti-herpes action. It has been previously reported by our research group that two new semisynthetic cardenolides, namely C10 (3ß-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin) and C11 (3ß-(hydroxyacetyl)amino-3-deoxydigitoxigenin), exhibited potential anti-HSV-1 and anti-HSV-2 with selectivity index values > 1,000, comparable with those of acyclovir. This work reports the mechanism investigation of anti-herpes action of these derivatives. The results demonstrated that C10 and C11 interfere with the intermediate and final steps of HSV replication, but not with the early stages, since they completely abolished the expression of the UL42 (ß) and gD (γ) proteins and partially reduced that of ICP27 (α). Additionally, they were not virucidal and had no prophylactic effects. Both compounds inhibited HSV replication at nanomolar concentrations, but cardenolide C10 was more active than C11 and can be considered as an anti-herpes drug candidate including against acyclovir-resistant HSV-1 strains.


Assuntos
Antivirais/farmacologia , Cardenolídeos/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Aciclovir/farmacologia , Animais , Antivirais/síntese química , Cardenolídeos/síntese química , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Infecções por Herpesviridae/tratamento farmacológico , Humanos , Células Vero
2.
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
3.
Prostate ; 80(4): 305-318, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31905252

RESUMO

BACKGROUND: Cardiac glycosides, which inhibit Na+ /K+ -ATPase, display inotropic effects for the treatment of congestive heart failure and cardiac arrhythmia. Recent studies have suggested signaling downstream of Na+ /K+ -ATPase action in the regulation of cell proliferation and apoptosis and have revealed the anticancer activity of cardiac glycosides. The study aims to characterize the anticancer potential of ascleposide, a natural cardenolide, and to uncover its primary target and underlying mechanism against human castration-resistant prostate cancer (CRPC). METHODS: Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay, carboxyfluorescein succinimidyl ester staining assay and clonogenic examination. Flow cytometric analysis was used to detect the distribution of cell cycle phase, mitochondrial membrane potential, intracellular Na+ and Ca2+ levels, and reactive oxygen species production. Protein expression was examined using Western blot analysis. Endocytosis of Na+ /K+ -ATPase was determined using confocal immunofluorescence microscopic examination. RESULTS: Ascleposide induced an increase of intracellular Na+ and a potent antiproliferative effect. It also induced a decrease of G1 phase distribution while an increase in both G2/M and apoptotic sub-G1 phases, and downregulated several cell cycle regulator proteins, including cyclins, Cdk, p21, and p27 Cip/Kip proteins, Rb and c-Myc. Ascleposide decreased the expression of antiapoptotic Bcl-2 members (eg, Bcl-2 and Mcl-1) but upregulated proapoptotic member (eg, Bak), leading to a significant loss of mitochondrial membrane potential and activation of both caspase-9 and caspase-3. Ascleposide also dramatically induced tubulin acetylation, leading to inhibition of the catalytic activity of Na+ /K+ -ATPase. Notably, extracellular high K+ (16 mM) significantly blunted ascleposide-mediated effects. Furthermore, ascleposide induced a p38 MAPK-dependent endocytosis of Na+ /K+ -ATPase and downregulated the protein expression of Na+ /K+ -ATPase α1 subunit. CONCLUSION: Ascleposide displays antiproliferative and apoptotic activities dependent on the inhibition of Na+ /K+ -ATPase pumping activity through p38 MAPK-mediated endocytosis of Na+ /K+ -ATPase and downregulation of α1 subunit, which in turn cause tubulin acetylation and cell cycle arrest. Cell apoptosis is ultimately triggered by the activation of caspase cascade attributed to mitochondrial damage through the downregulation of Bcl-2 and Mcl-1 protein expressions while upregulation of Bak protein levels. The data also suggest the potential of ascleposide in anti-CRPC development.


Assuntos
Cardenolídeos/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Tubulina (Proteína)/metabolismo , Acetilação/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Humanos , Masculino , Malvaceae/química , Células PC-3 , Extratos Vegetais/farmacologia , Neoplasias de Próstata Resistentes à Castração/patologia , Transdução de Sinais/efeitos dos fármacos
4.
Curr Pharm Biotechnol ; 21(1): 37-44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31530258

RESUMO

BACKGROUND: 17ßH-neriifolin, a cardiac glycoside compound had been successfully isolated from Cerbera odollam leaves based on the bioassay guided-isolation procedure. The aim of these studies were to determine the in vitro anti-cancer and binding effects of 17ßH-neriifolin on Na+, K+-ATPase. METHODS: The in vitro anti-cancer effects were evaluated using Sulphorhodamine B and Hoescht 33342 assays. The Na+, K+-ATPase assay was carried out using Malachite Green assay. In silico molecular docking studies and in vitro malachite green assay were used to predict the binding activities of 17ßH-neriifolin on Na+, K+-ATPase and ouabain was also included as for comparison studies. RESULTS: The compound was tested against breast (MCF-7, T47D), colorectal (HT-29), ovarian (A2780, SKOV-3) and skin (A375) cancer cell lines that gave IC50 values ranged from 0.022 ± 0.0015 to 0.030 ± 0.0018 µM. The mechanism of cell death of 17ßH-neriifolin was further evaluated using Hoescht 33342 assay and it was found that the compound killed the cancer cells via apoptosis. 17ßHneriifolin and ouabain both bound at α-subunit in Na+, K+-ATPase and their binding energy were - 8.16 ± 0.74 kcal/mol and -8.18 ± 0.48 kcal/mol respectively. CONCLUSION: The results had confirmed the anti-proliferative effects exerted by 17ßH-neriifolin in the breast, colorectal, ovarian and skin cancer cell lines. 17ßH-neriifolin had shown to cause apoptotic cell death in the respective cancer cell lines.17ßH-neriifolin and ouabain both bound at α-subunit in Na+, K+-ATPase and their binding energy were -8.16 ± 0.74 kcal/mol and -8.18 ± 0.48 kcal/mol respectively. This is the first report to reveal that 17ßH-neriifolin managed to bind to the pocket of α-subunit of Na+.K+-ATPase.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Cardenolídeos/farmacologia , Neoplasias Colorretais/metabolismo , Neoplasias Ovarianas/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Apocynaceae , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Simulação de Acoplamento Molecular , Neoplasias Ovarianas/tratamento farmacológico
5.
Life Sci ; 241: 117147, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830480

RESUMO

AIM: To investigate the cytotoxic effect of Peruvoside and mechanism of action in human cancers. MAIN METHODS: Cell viability was measured by MTT assay and the cell cycle arrest was identified by FACS. Real-time qPCR and western blotting studies were performed to identify important gene and protein expressions in the different pathways leading to apoptosis. Immunofluorescence was performed to understand protein localization and molecular docking studies were performed to identify protein-ligand interactions. KEY FINDINGS: Peruvoside showed significant anti-proliferative activities against human breast, lung, and liver cancer cells in dose-dependent manner. The anti-cancer mechanism was further confirmed by DNA damage and cell cycle arrest at the G0/G1 phase. Dysregulation of Wnt/ß-catenin signaling with Peruvoside treatment resulted in inhibition of cyclin D1 and c-Myc also observed in this study. Furthermore, we identified that Peruvoside can inhibit autophagy by PI3K/AKT/mTOR signaling and through downregulating MEK1. Moreover, Peruvoside has the ability to modulate the expressions of key proteins from the cell cycle, MAPK, NF-kB, and JAK-STAT signaling. In silico studies revealed that Peruvoside has the ability to interact with crucial proteins from different biochemical signaling pathways. SIGNIFICANCE: Our results demonstrated that Peruvoside has the ability to inhibit cancer cell proliferation by modulating the expression of various key proteins involved in cell cycle arrest, apoptosis, and autophagic cell death. Clinical data generated from the present study might provide a novel impetus for targeting several human cancers. Conclusively, our findings suggest that the Peruvoside possesses a broad spectrum of anticancer activity in breast, lung, and liver cancers, which provides an impetus for further investigation of the anticancer potentiality of this biomolecule.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia , Cardenolídeos/farmacologia , Cardiotônicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
6.
Ecology ; 100(12): e02857, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31365759

RESUMO

Inducible defense is a common form of phenotypic plasticity, and inducibility (change in defense after herbivore attack) has long been predicted to trade off with constitutive (or baseline) defense to manage resource allocation. Although such trade-offs likely constrain evolution within species, the extent to which they influence divergence among species is unresolved. We studied cardenolide toxins among genetic families in eight North American Asclepias species, spanning the full range of defense in the genus. Using common environment experiments and chemical assays, we report a consistent trade-off (negative genetic correlation) between concentrations of constitutive cardenolides and their inducibility within each species. However, no trade-off was found in a phylogenetic analysis across species. To investigate factors driving differences in defense allocation among species we used latitude as a proxy for growing season and herbivore pressure and found that divergence into lower latitudes resulted in evolution of higher cardenolides overall. Next we used an enzymatic assay of the cellular target of cardenolides (sodium-potassium ATPase) and confirm that higher cardenolides resulted in stronger toxicity to a sensitive species, but not to specialized monarch butterflies. Thus, plant speciation into biogeographic regions with alternative resources or pest pressure resulted in the macroevolution of cardenolide defense, especially against unspecialized herbivores. Nonetheless, trade-offs persist in the extent to which this defense is allocated constitutively or is inducible among genotypes within each species.


Assuntos
Asclepias , Borboletas , Animais , Cardenolídeos , Herbivoria , Filogenia
7.
J Chem Ecol ; 45(7): 610-625, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31281942

RESUMO

Plants use volatile organic compounds (VOCs) to cue natural enemies to their herbivore prey on plants. Simultaneously, herbivores utilize volatile cues to identify appropriate hosts. Despite extensive efforts to understand sources of variation in plant communication by VOCs, we lack an understanding of how ubiquitous belowground mutualists, such as arbuscular mycorrhizal fungi (AMF), influence plant VOC emissions. In a full factorial experiment, we subjected plants of two milkweed (Asclepias) species under three levels of AMF availability to damage by aphids (Aphis nerii). We then measured plant headspace volatiles and chemical defenses (cardenolides) and compared these to VOCs emitted and cardenolides produced by plants without herbivores. We found that AMF have plant species-specific effects on constitutive and aphid-induced VOC emissions. High AMF availability increased emissions of total VOCs, two green leaf volatiles (3-hexenyl acetate and hexyl acetate), and methyl salicylate in A. curassavica, but did not affect emissions in A. incarnata. In contrast, aphids consistently increased emissions of 6-methyl-5-hepten-2-one and benzeneacetaldehyde in both species, independent of AMF availability. Both high AMF availability and aphids alone suppressed emissions of individual terpenes. However, aphid damage on plants under high AMF availability increased, or did not affect, emissions of those terpenes. Lastly, aphid feeding suppressed cardenolide concentrations only in A. curassavica, and AMF did not affect cardenolides in either plant species. Our findings suggest that by altering milkweed VOC profiles, AMF may affect both herbivore performance and natural enemy attraction.


Assuntos
Afídeos/fisiologia , Asclepias/química , Micorrizas/fisiologia , Compostos Orgânicos Voláteis/análise , Animais , Asclepias/metabolismo , Asclepias/parasitologia , Cardenolídeos/análise , Cromatografia Gasosa-Espectrometria de Massas , Herbivoria , Interações entre Hospedeiro e Microrganismos , Interações Hospedeiro-Parasita , Folhas de Planta/química , Folhas de Planta/metabolismo , Folhas de Planta/parasitologia , Análise de Componente Principal
8.
Eur J Med Chem ; 180: 417-429, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325787

RESUMO

Oleandrin, the major biologically active constituent of shrub Nerium oleander preparations of which have been used in traditional Mediterranean and Asian medicine, attracts a great deal of attention due to its pronounced anticancer activity. The synthesis of oleandrigenin model, 16ß-hydroxy-3ß-methoxy-5α-card-20(22)-enolide 16-acetate, from androstenolone acetate through 17ß-(3-furyl)-intermediates has been developed. Several related 17ß-(butenolidyl)- and 17ß-(furyl)-androstane derivatives were synthesized and tested for in vitro cytotoxic and Na+/K+-ATP-ase inhibitory activities. Comparison of Na+/K+-ATP-ase inhibitory and cytotoxic activity underlines complex nature of the relationship.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cardenolídeos/farmacologia , Inibidores Enzimáticos/farmacologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Cardenolídeos/síntese química , Cardenolídeos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Conformação Molecular , Nerium/química , ATPase Trocadora de Sódio-Potássio/metabolismo , Relação Estrutura-Atividade
9.
Planta Med ; 85(11-12): 965-972, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31250411

RESUMO

Three previously undescribed cardenolides, acovenosigenin A 3-O-α-L-acofriopyranoside (1: ), 14-anhydroacovenosigenin A 3-O-[ß-D-glucopyranosyl-(1″→4')-O-α-L-acofriopyranoside] (2: ), and 14-anhydroacovenosigenin A 3-O-[ß-D-glucopyranosyl-(1″→4')-O-α-L-acovenopyranoside] (3: ), together with the two already known ones, 14-anhydrodigitoxigenin 3-O-ß-D-glucopyranoside (4: ) and acospectoside A (5: ), were isolated from the leaves of Acokanthera oblongifolia. The influence of cardenolides 1:  - 3: and acovenoside A (found in the Acokanthera genus) on three cancer cell lines (HT29, HCT116, and AGS) was also investigated. The most promising results, in comparison with oxaliplatin, were obtained for compound 1: , which was found to be highly cytotoxic for all tested cell lines, HT29 (IC50 = 63.49 nM), HCT116 (IC50 = 67.35 nM), and AGS (IC50 = 80.92 nM). Unfortunately, 1: also showed similar toxicity towards normal lymphocytes (IC50 = 98.03 nM).


Assuntos
Apocynaceae/química , Cardenolídeos/isolamento & purificação , Citotoxinas/isolamento & purificação , Folhas de Planta/química , Cardenolídeos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Citotoxinas/farmacologia , Humanos , Linfócitos/efeitos dos fármacos
10.
Philos Trans R Soc Lond B Biol Sci ; 374(1777): 20180246, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31154978

RESUMO

The repeated evolutionary specialization of distantly related insects to cardenolide-containing host plants provides a stunning example of parallel adaptation. Hundreds of herbivorous insect species have independently evolved insensitivity to cardenolides, which are potent inhibitors of the alpha-subunit of Na+,K+-ATPase (ATPα). Previous studies investigating ATPα-mediated cardenolide insensitivity in five insect orders have revealed remarkably high levels of parallelism in the evolution of this trait, including the frequent occurrence of parallel amino acid substitutions at two sites and recurrent episodes of duplication followed by neo-functionalization. Here we add data for a sixth insect order, Orthoptera, which includes an ancient group of highly aposematic cardenolide-sequestering grasshoppers in the family Pyrgomorphidae. We find that Orthopterans exhibit largely predictable patterns of evolution of insensitivity established by sampling other insect orders. Taken together the data lend further support to the proposal that negative pleiotropic constraints are a key determinant in the evolution of cardenolide insensitivity in insects. Furthermore, analysis of our expanded taxonomic survey implicates positive selection acting on site 111 of cardenolide-sequestering species with a single-copy of ATPα, and sites 115, 118 and 122 in lineages with neo-functionalized duplicate copies, all of which are sites of frequent parallel amino acid substitution. This article is part of the theme issue 'Convergent evolution in the genomics era: new insights and directions'.


Assuntos
Cardenolídeos/farmacologia , Herbivoria/efeitos dos fármacos , Herbivoria/genética , Resistência a Inseticidas , Inseticidas/farmacologia , Ortópteros/efeitos dos fármacos , Ortópteros/genética , Sequência de Aminoácidos , Animais , Evolução Biológica , Herbivoria/classificação , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Insetos/química , Insetos/classificação , Insetos/genética , Ortópteros/química , Ortópteros/classificação , Filogenia , Alinhamento de Sequência , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo
11.
J Forensic Leg Med ; 65: 133-136, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153008

RESUMO

BACKGROUND: Benefits and even dangers of plants are known since time began. The ancients used plants and herbs because of their effects on the human body. Poisoning is a logical consequence of their use: history is full of episodes of plants and herbs poisoning, whether intentional or accidental. AIM: Oleander poisoning is generally accidental; an intentional assumption of its leaves to commit suicide is uncommon because the population is not aware of the harmfulness of its cardiotoxic glycosides, therefore we report a fatal case of self-poisoning through the voluntary ingestion of oleander leaves. METHODS: A diagnosis of oleander self-poisoning was highly suspected on the basis of the circumstantial evidence and the autopsy findings. Toxicological investigations were performed on the samples collected during the autopsy and aimed at confirm the presence of oleandrin at a toxic level. RESULTS: The autopsy revealed a piece of oleander leaf on the posterior third of the tongue's body and several plant residues, similar to the one recovered on the tongue, into the gastric content; petechiae on the deep surface of the scalp, multi-organ congestion, and pulmonary edema were also observed. The histological study corroborated the pulmonary edema macroscopically observed but did not provide any other information. The detection of oleandrin in biological cadaveric samples revealed high, fatal, concentrations. CONCLUSIONS: Cases of voluntary ingestion of oleander with a suicidal intent prove to be uncommon: in the case reported the victim was aware about the possibility to commit suicide through the ingestion of oleander leaves.


Assuntos
Nerium/envenenamento , Folhas de Planta/envenenamento , Suicídio , Química Encefálica , Cardenolídeos/análise , Feminino , Vesícula Biliar/química , Mucosa Gástrica/química , Conteúdo Gastrointestinal/química , Humanos , Rim/química , Fígado/química , Pulmão/química , Pessoa de Meia-Idade , Edema Pulmonar/patologia , Baço/química
12.
Ecol Lett ; 22(9): 1396-1406, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31209991

RESUMO

Quantitatively linking individual variation in functional traits to demography is a necessary step to advance our understanding of trait-based ecological processes. We constructed a population model for Asclepias syriaca to identify how functional traits affect vital rates and population growth and whether trade-offs in chemical defence and demography alter population growth. Plants with higher foliar cardenolides had lower fibre, cellulose and lignin levels, as well as decreased sexual and clonal reproduction. Average cardenolide concentrations had the strongest effect on population growth. In both the sexual and clonal pathway, the trade-off between reproduction and defence affected population growth. We found that both increasing the mean of the distribution of individual plant values for cardenolides and herbivory decreased population growth. However, increasing the variance in both defence and herbivory increased population growth. Functional traits can impact population growth and quantifying individual-level variation in traits should be included in assessments of population-level processes.


Assuntos
Asclepias/química , Asclepias/fisiologia , Cardenolídeos/análise , Herbivoria , Densidade Demográfica , Reprodução , Virginia
13.
Phytother Res ; 33(7): 1837-1850, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050072

RESUMO

A major problem in osteosarcoma treatment is cisplatin resistance. We have reported the anti-osteosarcoma effect of oleandrin; however, whether oleandrin sensitizes osteosarcoma to cisplatin is unknown. We investigated the chemosensitization of oleandrin and potential mechanisms in osteosarcoma cells U-2OS, SaOS-2, and MG-63. The median-effect analysis demonstrated that cisplatin + oleandrin exerted synergistic (U-2OS and MG-63) or additive effects (SaOS-2), which were consistent with the changes of the intracellular accumulation of platinum (Pt) and Pt-DNA adducts. Immunohistochemistry staining showed that the expression level of the mature form CTR1, the major influx transporter of cisplatin, was low in osteosarcoma tissue. However, oleandrin with or without cisplatin significantly increased the expression and membrane localization of the mature CTR1. Furthermore, CTR1 knockdown reversed the synergistic effect and decreased cisplatin uptake. The mRNA microarray analysis suggested that oleandrin downregulated the expression of proteasome-related genes, which was verified by the proteasome activity assay. Besides, the proteasome inhibitor MG132 upregulated the expression of the mature CTR1 in U-2OS and MG-63 cells. Overall, we conclude that oleandrin sensitizes osteosarcoma cells to cisplatin in synergistic or additive manners. The synergy results from the enhanced cisplatin uptake via oleandrin-mediated inhibition of proteasome activity and subsequent blockage of the mature CTR1 degradation.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Cardenolídeos/farmacologia , Proteínas de Transporte de Cátions/metabolismo , Cisplatino/farmacologia , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Transportador de Cobre 1 , Humanos , Osteossarcoma/metabolismo
14.
Cancer Lett ; 453: 57-73, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30930233

RESUMO

Natural products possess a significant role in anticancer therapy and many currently-used anticancer drugs are of natural origin. Cerberin (CR), a cardenolide isolated from the fruit kernel of Cerbera odollam, was found to potently inhibit cancer cell growth (GI50 values < 90 nM), colony formation and migration. Significant G2/M cell cycle arrest preceded time- and dose-dependent apoptosis-induction in human cancer cell lines corroborated by dose-and time-dependent PARP cleavage and caspase 3/7 activation, in addition to reduced Bcl-2 and Mcl-1 expression. CR potently inhibited PI3K/AKT/mTOR signalling depleting polo-like kinase 1 (PLK-1), c-Myc and STAT-3 expression. Additionally, CR significantly increased the generation of reactive oxygen species (ROS) producing DNA double strand breaks. Preliminary in silico biopharmaceutical assessment of CR predicted >60% bioavailability and rapid absorption; doses of 1-10 mg/kg CR were predicted to maintain efficacious unbound plasma concentrations (>GI50 value). CR's potent and selective anti-tumour activity, and its targeting of key signalling mechanisms pertinent to tumourigenesis support further preclinical evaluation of this cardiac glycoside.


Assuntos
Cardenolídeos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cardenolídeos/química , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Células HCT116 , Células HT29 , Células Hep G2 , Humanos , Células MCF-7 , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo
15.
J Antibiot (Tokyo) ; 72(6): 437-448, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30948784

RESUMO

This manuscript describes a single pot protocol for the selective introduction of unprotected sugars to the C3 position of the cardiotonic steroid strophanthidol. These reactions proceed with high levels of regiocontrol (>20:1 rr) in the presence of three other hydroxyl functionalities including the C19 primary hydroxyl group and could be applied to different sugars to provide the deprotected cardiac glycosides upon work up (5 examples, 77-69% yield per single operation). The selective glycosylation of the less reactive C3 position is accomplished by the use of traceless protection with methylboronic acid that blocks the C5 and C19 hydroxyls by forming a cyclic boronic ester, followed by in situ glycosylation and a work up with ammonia in methanol to remove the boronic ester and the carbohydrate ester protecting groups.


Assuntos
Compostos de Boro/química , Cardenolídeos/química , Glicosídeos/química , Glicosilação , Estrutura Molecular
16.
Nutrients ; 11(3)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836643

RESUMO

Elaeodendron transvaalense is a plant species, which is in high demand as a herbal medicine in southern Africa. This study critically reviewed the medicinal applications, phytochemistry and pharmacological activities of E. transvaalense. The literature on medicinal applications, phytochemical, and pharmacological activities of E. transvaalense, was collected from multiple internet sources including Elsevier, Google Scholar, SciFinder, Web of Science, Pubmed, BMC, Science Direct, and Scopus. Complementary information was gathered from pre-electronic sources, such as books, book chapters, theses, scientific reports, and journal articles obtained from the University library. This study revealed that the species is used as herbal medicine in 62.5% of the countries where E. transvaalense is native in southern Africa. It is mainly used as herbal medicine for diarrhoea, menorrhagia, stomach aches, skin infections, inflammations, and rashes. Phytochemical compounds identified from the species, include flavonoids, peltogynoid, phenols, proanthocyanidins, tannin, and triterpenes. Ethnopharmacological research revealed that extracts and phytochemical constituents isolated from E. transvaalense have antibacterial, antifungal, anti-HIV, anti-inflammatory, antioxidant, antiplasmodial, anti-protozoan, anti-pyretic, hypoglycaemic, larvicidal, cytotoxicity, and mutagenic activities. Elaeodendron transvalense should to be subjected to detailed phytochemical, pharmacological, and toxicological evaluations aimed at correlating the medicinal uses of the species with the ethnopharmacological properties of the species.


Assuntos
Cardenolídeos/farmacologia , Etnofarmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , África Austral , Humanos , Fitoterapia
17.
Pest Manag Sci ; 75(10): 2770-2775, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30838743

RESUMO

BACKGROUND: Terrestrial mollusks are one of most important agricultural pests worldwide. Natural phytochemicals have an extended history as a source of pesticides. This study was planned to isolate molluscicidal active compounds from the stems of Adenium obesum. RESULTS: The benzene-soluble fraction of the hydroethanolic extract displayed the most potent molluscicidal activity against Monacha obstructa among different solvent fractions with a median lethal dose (LD50 ) of 4.91 µg g-1 body weight (bw). The bioactivity-guided chemical exploration of the benzene-soluble fraction led to the isolation of two known cardiac glycosides, cerberin and neriifolin which showed significant molluscicidal activity with LD50 values of 5.39 and 4.3 µg g-1 bw, respectively. CONCLUSION: Isolation of the cardiac glycoside neriifolin from A. obesum and the molluscicidal activity of cerberin and neriifolin against terrestrial snails are reported for the first time. © 2019 Society of Chemical Industry.


Assuntos
Apocynaceae/química , Cardenolídeos/farmacologia , Glicosídeos Cardíacos/farmacologia , Moluscocidas/farmacologia , Caramujos/efeitos dos fármacos , Animais , Dose Letal Mediana , Extratos Vegetais/farmacologia , Caules de Planta/química
18.
Int J Syst Evol Microbiol ; 69(4): 1220-1224, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30785392

RESUMO

We isolated five novel bacterial strains from symptomatic bark tissue of Populus × euramericana canker that were Gram-stain-negative, non-motile, aerobic oxidase-negative and catalase-positive. Growth occurred at 10-41 °C and at pH 5.0-7.0, with optimum growth at 30 °C and pH 7.0. Additionally, growth occurred in conditions of 0-5 % (w/v) salinity, but not above 7 % NaCl. The 16S rRNA gene sequences of the novel strains shared the highest similarity with Sinorhodobacter ferrireducens SgZ-3T (97.1 %). The average nucleotide identity values between the novel strains and two type strains (S.inorhodobacter ferrireducens CCTCC AB2012026T and 'Sinorhodobacter hungdaonensis' CGMCC 1.12963T) were 78.4-78.9 %, which were lower than the proposed species boundary cut-off (95-96 %). The main polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified lipid and phosphatidylcholine. The main respiratory quinone was Q-10, and major fatty acids were C18 : 1ω7c and/or C18 : 1ω6c. Based on data from a polyphasic taxonomy study, the novel strains represent a novel species of the genus Sinorhodobacter, for which the name Sinorhodobacter populi sp. nov. is proposed. The type strain is sk2b1T (=CFCC 14580T=KCTC 52802T).


Assuntos
Filogenia , Casca de Planta/microbiologia , Doenças das Plantas/microbiologia , Populus/microbiologia , Rhodobacteraceae/classificação , Técnicas de Tipagem Bacteriana , Composição de Bases , Cardenolídeos/química , China , DNA Bacteriano/genética , Ácidos Graxos/química , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Rhodobacteraceae/isolamento & purificação , Análise de Sequência de DNA
19.
J Chem Ecol ; 45(3): 264-277, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30793231

RESUMO

Monarch butterflies, Danaus plexippus, migrate long distances over which they encounter host plants that vary broadly in toxic cardenolides. Remarkably little is understood about the mechanisms of sequestration in Lepidoptera that lay eggs on host plants ranging in such toxins. Using closely-related milkweed host plants that differ more than ten-fold in cardenolide concentrations, we mechanistically address the intake, sequestration, and excretion of cardenolides by monarchs. We show that on high cardenolide plant species, adult butterflies saturate in cardenolides, resulting in lower concentrations than in leaves, while on low cardenolide plants, butterflies concentrate toxins. Butterflies appear to focus their sequestration on particular compounds, as the diversity of cardenolides is highest in plant leaves, lower in frass, and least in adult butterflies. Among the variety of cardenolides produced by the plant, sequestered compounds may be less toxic to the butterflies themselves, as they are more polar on average than those in leaves. In accordance with this, results from an in vitro assay based on inhibition of Na+/K+ ATPase (the physiological target of cardenolides) showed that on two milkweed species, including the high cardenolide A. perennis, extracts from butterflies have lower inhibitory effects than leaves when standardized by cardenolide concentration, indicating selective sequestration of less toxic compounds from these host plants. To understand how ontogeny shapes sequestration, we examined cardenolide concentrations in caterpillar body tissues and hemolymph over the course of development. Caterpillars sequestered higher concentrations of cardenolides as early instars than as late instars, but within the fifth instar, concentration increased with body mass. Although it appears that large amounts of sequestration occurs in early instars, a host switching experiment revealed that caterpillars can compensate for feeding on low cardenolide host plants with substantial sequestration in the fifth instar. We highlight commonalities and striking differences in the mechanisms of sequestration depending on host plant chemistry and developmental stage, which have important implications for monarch defense.


Assuntos
Borboletas/metabolismo , Cardenolídeos/metabolismo , Larva/crescimento & desenvolvimento , Animais , Borboletas/crescimento & desenvolvimento , Cromatografia Líquida de Alta Pressão , Feminino , Masculino
20.
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
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