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1.
Nutrients ; 13(12)2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34959790

RESUMO

Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against Amanita phalloides intoxication, only inconclusive data are available for alcoholic liver damage. Since silymarin flavonolignans have metal-chelating activity, we hypothesized that silymarin may influence alcoholic liver damage by inhibiting zinc-containing alcohol dehydrogenase (ADH). Therefore, we tested the zinc-chelating activity of pure silymarin flavonolignans and their effect on yeast and equine ADH. The most active compounds were also tested on bovine glutamate dehydrogenase, an enzyme blocked by zinc ions. Of the six flavonolignans tested, only 2,3-dehydroderivatives (2,3-dehydrosilybin and 2,3-dehydrosilychristin) significantly chelated zinc ions. Their effect on yeast ADH was modest but stronger than that of the clinically used ADH inhibitor fomepizole. In contrast, fomepizole strongly blocked mammalian (equine) ADH. 2,3-Dehydrosilybin at low micromolar concentrations also partially inhibited this enzyme. These results were confirmed by in silico docking of active dehydroflavonolignans with equine ADH. Glutamate dehydrogenase activity was decreased by zinc ions in a concentration-dependent manner, and this inhibition was abolished by a standard zinc chelating agent. In contrast, 2,3-dehydroflavonolignans blocked the enzyme both in the absence and presence of zinc ions. Therefore, 2,3-dehydrosilybin might have a biologically relevant inhibitory effect on ADH and glutamate dehydrogenase.


Assuntos
Álcool Desidrogenase/antagonistas & inibidores , Quelantes/farmacologia , Flavonolignanos/farmacologia , Silimarina/farmacologia , Zinco/isolamento & purificação , Animais , Glutamato Desidrogenase/antagonistas & inibidores , Cavalos , Silibina/farmacologia , Leveduras/efeitos dos fármacos , Zinco/metabolismo
2.
Exp Biol Med (Maywood) ; 246(13): 1541-1553, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33926261

RESUMO

Hydnocarpin D (HD) is a bioactive flavonolignan compound that possesses promising anti-tumor activity, although the mechanism is not fully understood. Using T cell acute lymphoblastic leukemia (T-ALL) cell lines Jurkat and Molt-4 as model system, we found that HD suppressed T-ALL proliferation in vitro, via induction of cell cycle arrest and subsequent apoptosis. Furthermore, HD increased the LC3-II levels and the formation of autophagolysosome vacuoles, both of which are markers for autophagy. The inhibition of autophagy by either knockdown of ATG5/7 or pre-treatment of 3-MA partially rescued HD-induced apoptosis, thus suggesting that autophagy enhanced the efficacy of HD. Interestingly, this cytotoxic autophagy triggered ferroptosis, as evidenced by the accumulation of lipid ROS and decrease of GSH and GPX4, while inhibition of autophagy impeded ferroptotic cell death. Our study suggests that HD triggers multiple cell death processes and is an interesting compound that should be evaluated in future preclinical studies.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Flavonolignanos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Ciclo Celular/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Células Jurkat , Espécies Reativas de Oxigênio/metabolismo
3.
Phytother Res ; 35(6): 3286-3297, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33587330

RESUMO

Silybum marianum (L.) Gaertn. (Asteraceae), commonly known as milk thistle, is a botanical natural product used to self-treat multiple diseases such as Type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH). An extract from milk thistle seeds (achenes), termed silymarin, is comprised primarily of several flavonolignans. Systemic concentrations of these flavonolignans can influence the potential biologic effects of silymarin and the risk for pharmacokinetic silymarin-drug interactions. The aims of this research were to determine the roles of organic anion transporting polypeptides (OATPs/Oatps) in silymarin flavonolignan disposition and in pharmacokinetic silymarin-drug interactions. The seven major flavonolignans from silymarin were determined to be substrates for OATP1B1, OATP1B3, and OATP2B1. Sprague Dawley rats were fed either a control diet or a NASH-inducing diet and administered pitavastatin (OATP/Oatp probe substrate), followed by silymarin via oral gavage. Decreased protein expression of Oatp1b2 and Oatp1a4 in NASH animals increased flavonolignan area under the plasma concentration-time curve (AUC) and maximum plasma concentration. The combination of silymarin inhibition of Oatps and NASH-associated decrease in Oatp expression caused an additive increase in plasma pitavastatin AUC in the animals. These data indicate that OATPs/Oatps contribute to flavonolignan cellular uptake and mediate the interaction between silymarin and NASH on pitavastatin systemic exposure.


Assuntos
Flavonolignanos/metabolismo , Cardo-Mariano/química , Transportadores de Ânions Orgânicos/metabolismo , Silimarina/metabolismo , Animais , Antioxidantes/metabolismo , Interações Medicamentosas , Flavonoides/metabolismo , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley
4.
Planta Med ; 87(5): 404-416, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33007785

RESUMO

It is well known that biotransformation processes in the human body are crucial to form potentially bioactive metabolites from particular classes of natural products. However, little research has been conducted concerning the bioavailability of polyphenols, especially in the colon. The gastrointestinal stability and colonic biotransformation of the crude extract of the leaves of Cecropia obtusifolia, rich in flavone C-glycosides, was investigated under in vitro conditions, and the processing and interpretation of results were facilitated by using an automated machine learning model. This investigation revealed that flavone C-glycosides and flavonolignans from C. obtusifolia were stable throughout their passage in the simulated gastrointestinal tract including the colon phase. On the other hand, the colon bacteria extensively metabolized chlorogenic acid, flavonol, and triterpenoid O-glycosides. This investigation revealed that the colonic microbiota has an important role in the biotransformation of some chemical constituents of this extract.


Assuntos
Flavonolignanos , Saponinas , Triterpenos , Biotransformação , Ácido Clorogênico/metabolismo , Flavonoides/metabolismo , Flavonolignanos/metabolismo , Trato Gastrointestinal/metabolismo , Saponinas/metabolismo , Triterpenos/metabolismo
5.
J Agric Food Chem ; 68(24): 6564-6575, 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32437606

RESUMO

The fruit of Hippophae rhamnoides L. has been used for centuries in Europe and Asia as a food with high nutritional and medicinal values. In this study, a bioactivity-guided phytochemical investigation of H. rhamnoides L. has resulted in four new dimethylallylated flavonolignans (1-4), four new isopropylpentenone-flavonolignan heterodimers (5-8), two new geranylated flavonolignans (9 and 10), and 14 known flavonolignan derivatives (11-24); they were elucidated by their spectrometric and spectroscopic methods, including HR-ESI-MS, NMR, IR, and UV from the fruit of H. rhamnoides L. for the first time. Among them, compounds 2, 5, 6, 20, and 21 showed potent immunosuppressive activities with IC50 values from 19.42 ± 3.91 to 48.05 ± 12.56 µM. Meanwhile, compounds 1, 4, 11, 12, and 13 showed moderate neuroprotective activities, which increased the cell survival rate from 50.30 ± 4.24% for the model group to 71.63 ± 3.04%, 70.02 ± 4.13%, 61.53 ± 5.93%, 61.08 ± 3.58%, and 65.68 ± 4.88% at 10 µM, respectively. The hypothetical biogenetic pathway and preliminary structure-activity relationship were found and discussed scientifically.


Assuntos
Flavonolignanos/química , Hippophae/química , Imunossupressores/química , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Flavonolignanos/farmacologia , Frutas/química , Humanos , Imunossupressores/farmacologia , Estrutura Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
6.
Fitoterapia ; 143: 104541, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32151639

RESUMO

Four flavanolignans, ceibapentains A (1) and B (2) and cinchonains Ia (3) and Ib (4), were isolated for the first time from an ethyl acetate extract of Ceiba pentandra (L) (Bombacaceae) aerial parts. The ceibapentains A (1) and B (2) are new compounds and their structures, including the absolute configurations, were determined by HRESIMS, 1D and 2D NMR, and electronic circular dichroism analyses, then compared with reported data. Compounds 1-4 were tested for their anti-Alzheimer's activity via an assessment of their inhibitory effect on amyloid ß42 aggregation using a thioflavin T assay. The results revealed that cinchonain Ia (3) showed a higher inhibitory effect (91%) than the standard curcumin (70%). Compounds 1, 2, and 4 exhibited moderate activity, with inhibition ratios of 43%, 47%, and 58%, respectively. A molecular docking study on the binding mode of 3 and curcumin with an amyloid ß1-40 peptide fibril structure indicated a high affinity of cinchonain 1a (3) towards amyloid ß1-40 peptide, in agreement with the experimental results.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Ceiba/química , Flavonolignanos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Dicroísmo Circular , Egito , Flavonolignanos/isolamento & purificação , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química , Extratos Vegetais/química
7.
Anticancer Agents Med Chem ; 20(15): 1817-1830, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31976848

RESUMO

BACKGROUND: The small chemical class of flavonolignans encompasses unique hybrid molecules with versatile biological activities. Their anticancer effects have received considerable attention, and a large body of supporting evidence has accumulated. Moreover, their ability to interact with proteins involved in drug resistance, and to enhance the effects of conventional chemotherapeutics in decreasing cell viability make them influential partners in addressing cancer. OBJECTIVE: The review provides an outline of the various ways in which flavonolignans advance the combat against cancer. While the main focus falls on flavonolignans from milk thistle, attention is drawn to the yet, underexplored potential of less known flavonolignan subgroups derived from isoflavonoids and aurones. METHODS: Proceeding from the presentation of natural flavonolignan subtypes and their occurrence, the present work reviews these compounds with regard to their molecular targets in cancer, anti-angiogenetic effects, synergistic efficacy in conjunction with anticancer agents, reversal of drug resistance, and importance in overcoming the side effects of anticancer therapy. Recent advances in the endeavor to improve flavonolignan bioavailability in cancer are also presented. CONCLUSIONS: Significant progress has been achieved in detailing the molecular mechanisms of silybin and its congeners in experimental models of cancer. The availability of novel formulations with improved bioavailability, and data from phase I clinical trials in cancer patients provide an encouraging basis for more extensive trials aimed at evaluating the benefits of Silybum flavonolignans in cancer management. On the other hand, further research on the antitumor efficacy of iso-flavonolignans and other subtypes of flavonolignans should be pursued.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flavonolignanos/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos Fitogênicos/química , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Flavonolignanos/química , Humanos , Cardo-Mariano/química , Estrutura Molecular , Neoplasias/patologia
8.
Anal Bioanal Chem ; 412(4): 819-832, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31919606

RESUMO

Silymarin, milk thistle (Silybum marianum) extract, contains a mixture of mostly isomeric bioactive flavonoids and flavonolignans that are extensively studied, especially for their possible liver-protective and anticancer effects. Because of the differing bioactivities of individual isomeric compounds, characterization of their proportion in a mixture is highly important for predicting its effect on health. However, because of silymarin's complexity, this is hardly feasible by common analytical techniques. In this work, ultraperformance liquid chromatography coupled with drift tube ion mobility spectrometry and quadrupole time-of-flight mass spectrometry was used. Eleven target silymarin compounds (taxifolin, isosilychristin, silychristins A and B, silydianin, silybins A and B, 2,3-cis-silybin B, isosilybins A and B and 2,3-dehydrosilybin) and five unknown flavonolignan isomers detected in the milk thistle extract were fully separated in a 14.5-min analysis run. All the compounds were characterized on the basis of their accurate mass, retention time, drift time, collision cross section and fragmentation spectra. The quantitative approach based on evaluation of the ion mobility data demonstrated lower detection limits, an extended linear range and total separation of interferences from the compounds of interest compared with the traditional approach based on evaluation of liquid chromatography-quadrupole time-of-flight mass spectrometry data. The following analysis of a batch of milk thistle-based food supplements revealed significant variability in the silymarin pattern, especially in the content of silychristin A and silybins A and B. This newly developed method might have high application potential, especially for the characterization of materials intended for bioactivity studies in which information on the exact silymarin composition plays a crucial role. Graphical Abstract.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Mobilidade Iônica/métodos , Cardo-Mariano/química , Silimarina/análise , Flavonolignanos/análise , Flavonolignanos/isolamento & purificação , Isomerismo , Espectrometria de Massas/métodos , Silimarina/isolamento & purificação
9.
J Agric Food Chem ; 68(7): 1763-1779, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30907588

RESUMO

Multidrug resistance (MDR) is a major challenge for the 21th century in both cancer chemotherapy and antibiotic treatment of bacterial infections. Efflux pumps and transport proteins play an important role in MDR. Compounds displaying inhibitory activity toward these proteins are prospective for adjuvant treatment of such conditions. Natural low-cost and nontoxic flavonoids, thanks to their vast structural diversity, offer a great pool of lead structures with broad possibility of chemical derivatizations. Various flavonoids were found to reverse both antineoplastic and bacterial multidrug resistance by inhibiting Adenosine triphosphate Binding Cassette (ABC)-transporters (human P-glycoprotein, multidrug resistance-associated protein MRP-1, breast cancer resistance protein, and bacterial ABC transporters), as well as other bacterial drug efflux pumps: major facilitator superfamily (MFS), multidrug and toxic compound extrusion (MATE), small multidrug resistance (SMR) and resistance-nodulation-cell-division (RND) transporters, and glucose transporters. Flavonoids and particularly flavonolignans are therefore highly prospective compounds for defying multidrug resistance.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Proteínas de Bactérias/antagonistas & inibidores , Farmacorresistência Bacteriana , Resistencia a Medicamentos Antineoplásicos , Flavonoides/administração & dosagem , Flavonolignanos/administração & dosagem , Neoplasias/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antibacterianos/farmacologia , Antineoplásicos/uso terapêutico , Bactérias/genética , Bactérias/metabolismo , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética
10.
Nat Prod Res ; 34(22): 3169-3175, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30618297

RESUMO

A series of novel flavonolignans were synthesized by the reaction between a lignan named samin (1) and a range of flavonoids. This simple and rapid approach allowed direct assembly of these two bulky motifs in good yields without the formation of byproducts. Upon evaluation of antidiabetic activity of the synthesized products, epicatechinosamin (ß-2g) was the most active α-glucosidase inhibitor toward maltase and sucrase. The kinetic study indicated that ß-2 g inhibited the enzymes in a mixed manner of competitive and noncompetitive inhibition.


Assuntos
Flavonolignanos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Flavonoides/química , Flavonolignanos/química , Radicais Livres/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Cinética , Espectroscopia de Ressonância Magnética , Estrutura Molecular , alfa-Glucosidases/metabolismo
11.
J Pharm Biomed Anal ; 178: 112972, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31727359

RESUMO

Silybum marianum (milk thistle) is a medicinal plant used for producing the hepatoprotective remedy silymarin. Its main bioactive constituents, including silybin and related flavonolignans, can be metabolized directly by phase II conjugation reactions. This study was designed to identify UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of six silymarin flavonolignans, namely silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin. UHPLC-MS analyses showed that all of the tested compounds, both individually and in silymarin, were glucuronidated by human liver microsomes, and that glucuronidation was the main metabolic transformation in human hepatocytes. Further, each compound was glucuronidated by multiple recombinant human UGT enzymes. UGTs 1A1, 1A3, 1A8 and 1A9 were able to conjugate all of the tested flavonolignans, and some of them were also metabolized by UGTs 1A6, 1A7, 1A10, 2B7 and 2B15. In contrast, no glucuronides were produced by UGTs 1A4, 2B4, 2B10 and 2B17. With silymarin, we found that UGT1A1 and, to a lesser extent UGT1A9, were primarily responsible for the glucuronidation of the flavonolignan constituents. It is concluded that the metabolism of silymarin flavonolignans may involve multiple UGT enzymes, of which UGT1A1 appears to play the major role in the glucuronidation. These results may be relevant for future research on the metabolism of flavonolignans in humans.


Assuntos
Flavonolignanos/metabolismo , Glucuronosiltransferase/metabolismo , Silimarina/metabolismo , Adulto , Células Cultivadas , Glucuronídeos/metabolismo , Hepatócitos/metabolismo , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Cardo-Mariano/metabolismo , Silibina/metabolismo , Silimarina/análogos & derivados
12.
Molecules ; 24(20)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615114

RESUMO

Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR-) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Hepatopatias/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Silimarina/uso terapêutico , Animais , Antioxidantes , Flavonolignanos/metabolismo , Humanos , Hepatopatias/genética , Hepatopatias/patologia , Cardo-Mariano/química , Fitoterapia , Ratos , Silibina/metabolismo
13.
Nutrients ; 11(10)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554252

RESUMO

Silymarin is a traditional drug and food supplement employed for numerous liver disorders. The available studies indicate that its activities may be broader, in particular due to claimed benefits in some cardiovascular diseases, but the contributions of individual silymarin components are unclear. Therefore, we tested silymarin flavonolignans as pure diastereomers as well as their sulfated metabolites for potential vasorelaxant and antiplatelet effects in isolated rat aorta and in human blood, respectively. Eleven compounds from a panel of 17 tested exhibited a vasorelaxant effect, with half maximal effective concentrations (EC50) ranging from 20 to 100 µM, and some substances retained certain activity even in the range of hundreds of nM. Stereomers A were generally more potent as vasorelaxants than stereomers B. Interestingly, the most active compound was a metabolite-silychristin-19-O-sulfate. Although initial experiments showed that silybin, 2,3-dehydrosilybin, and 2,3-dehydrosilychristin were able to substantially block platelet aggregation, their effects were rapidly abolished with decreasing concentration, and were negligible at concentrations ≤100 µM. In conclusion, metabolites of silymarin flavonolignans seem to have biologically relevant vasodilatory properties, but the effect of silymarin components on platelets is low or negligible.


Assuntos
Aorta/efeitos dos fármacos , Flavonolignanos/química , Flavonolignanos/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Humanos , Masculino , Estrutura Molecular , Ratos , Vasodilatadores
14.
J Med Chem ; 62(17): 8311-8329, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31393121

RESUMO

Hydnocarpin (Hy) is a flavonoid isolated and purified from the seeds of Hydnocarpus wightiana Blume. Herein, we have developed a built-in semi-synthetic modification on Hy by one-pot multi-component reaction and a [3 + 2] cycloaddition strategy to append five membered isoxazole and isoxazolone as new phytochemical entities (NPCEs). Two selected NPCEs viz Hy-ISO-VIII and Hy-ISO-G from the library of 20 newly synthesized derivatives after in vitro screening unveiled promising cytotoxicity and induced caspase-mediated apoptosis against the human lung and melanoma cancer cells which were well supported by virtual screening based on ligand binding affinity and molecular dynamic simulations. As a new insight, we introduced surface-enhanced Raman spectroscopy to identify the chemo-marker molecular fingerprint to confirm the cellular uptake, cytochrome c release, and DNA fragmentation in a label-free manner. The present findings throw up a surfeit of seminal reasons behind the semi-synthetic modification of Hy, stepping forward to cancer chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Citocromos c/antagonistas & inibidores , Flavonolignanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Reação de Cicloadição , Citocromos c/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flavonolignanos/síntese química , Flavonolignanos/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Melanoma/metabolismo , Melanoma/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
15.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010179

RESUMO

Silymarin flavonolignans are well-known agents that typically possess antioxidative, anti-inflammatory, and hepatoprotective functions. Recent studies have also documented the antiviral activities of silymarin and its derivatives against several viruses, including the flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunya virus and Mayaro virus), influenza virus, human immunodeficiency virus, and hepatitis B virus. This review will describe some of the latest preclinical and clinical studies detailing the antiviral profiles of silymarin and its derivatives, and discuss their relevance for antiviral drug development.


Assuntos
Antivirais/farmacologia , Flavonolignanos/farmacologia , Silimarina/farmacologia , Antivirais/química , Vírus Chikungunya/efeitos dos fármacos , Vírus da Dengue/efeitos dos fármacos , Flavivirus/efeitos dos fármacos , Flavonolignanos/química , HIV/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Silimarina/química , Togaviridae/efeitos dos fármacos
16.
Molecules ; 24(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875758

RESUMO

Silybum marianum (L.) is a medicinal plant traditionally used in treatment of liver disorders. In last decades, silymarin (SM), a standardized extract from S. marianum seeds has been studied for its dermatological application, namely for UVB-protective properties. However, information on SM and its polyphenols effect on activity of enzymes participating in the (photo)aging process is limited. Therefore, evaluation of SM and its flavonolignans potential to inhibit collagenase, elastase, and hyaluronidase in tube tests was the goal of this study. The antioxidant and UV screening properties of SM and its flavonolignans silybin, isosilybin, silydianin, silychristin and 2,3-dehydrosilybin (DHSB) were also evaluated by a DPPH assay and spectrophotometrical measurement. DHSB showed the highest ability to scavenge DPPH radical and also revealed the highest UVA protection factor (PF-UVA) that corresponds with its absorption spectrum. SM and studied flavonolignans were found to exhibit anti-collagenase and anti-elastase activity. The most potent flavonolignan was DHSB. None of studied flavonolignans or SM showed anti-hyaluronidase activity. Our results suggest that SM and its flavonolignans may be useful agents for skin protection against the harmful effects of full-spectrum solar radiation including slowing down skin (photo)aging.


Assuntos
Flavonolignanos/química , Extratos Vegetais/química , Silimarina/química , Pele/efeitos dos fármacos , Antioxidantes/química , Antioxidantes/isolamento & purificação , Flavonolignanos/isolamento & purificação , Humanos , Cardo-Mariano/química , Sementes/química , Silimarina/isolamento & purificação , Pele/patologia , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos
17.
J Chromatogr Sci ; 57(5): 418-425, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753465

RESUMO

Herbal plants are significant for the reason that they have a great potential in discovering drug precursors. However, how to purify compounds with higher purity from them is a question which needs to be discussed. In present study, an offline 2D reversed-phase (RP) preparative liquid chromatography coupled with solid-phase extraction (SPE) method was successfully developed for the separation of flavonolignan diastereoisomers from Arenaria kansuensis. Based on the analysis of results, the major conclusion that we have drawn from it is a RP-SPE was selected for enriching target flavonolignan sample from A. kansuensis. After that, an ODS preparative column was used for 1D preparation, and the target sample (4.6 g) was divided into five fractions with a recovery of 83.9%. Then, a C18HCE preparative column, a polar-modified RP (polar-copolymerized) type, was used for isolating flavonolignan diastereoisomers in the 2D preparation. By establishing optimal 2D chromatography, hydrophilic interaction chromatography (HILIC) columns and normal-phase (NP) columns were tested simultaneously, and the result showed that diastereoisomers are not suitable for HILIC and NP chromatography mode. Our study resulted in a tricin and five analogous derivative flavonolignans with purity >98% were successfully purified from A. kansuensis. This is the initial report of Salcolin C, Salcolin B, Tricin 4'-O-(C-veratroylglycol) ether and 5'-methoxyhydnocarpin D from A. kansuensis. In addition, it tended to be the first time that Tricin 4'-O-(C-veratroylglycol) ether is isolated from natural resource. This method has great potential for efficiently isolating flavonolignan diastereoisomers from A. kansuensis, and it shows a great prospect for the separation of flavonolignans from complex samples.


Assuntos
Arenaria (Planta)/química , Cromatografia de Fase Reversa/métodos , Flavonolignanos/análise , Flavonolignanos/isolamento & purificação , Extratos Vegetais/análise , Extratos Vegetais/isolamento & purificação , Extração em Fase Sólida/métodos , Estereoisomerismo
18.
Fitoterapia ; 134: 81-87, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30690126

RESUMO

In this study, a new flavonolignan vernicilignan A was isolated from Toxicodendron vernicifluum. The neuroprotective effects of this compound against H2O2 induced cell injury in SH-SY5Y cells were evaluated by MTT assay and LDH release assay. Vernicilignan A dose-dependently attenuated the cell injury and LDH release induced by H2O2 in SH-SY5Y cells. Further study indicated that vernicilignan A reduced cell apoptosis caused by H2O2 treatment via regulation of some apoptotic related proteins including Bax, Bcl-2, caspase 3 and caspase 9. Also, vernicilignan A increase the cell viability of H2O2 treated cells via the activation of Akt and GSK3ß. Base on the findings, vernicilignan A exhibited neuroprotective effects through the activation of PI3K/Akt signaling and inhibition of mitochondria apoptosis pathway. Vernicilignan A might be a promising therapeutic agent for oxidative stress induced neurodegenerative diseases.


Assuntos
Flavonolignanos/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Toxicodendron/química , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular , Sobrevivência Celular , China , Flavonolignanos/isolamento & purificação , Humanos , Peróxido de Hidrogênio , Mitocôndrias , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Fosfatidilinositol 3-Quinases/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Madeira/química , Proteína X Associada a bcl-2/metabolismo
19.
Phytomedicine ; 53: 79-85, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668415

RESUMO

BACKGROUND: In recent years the number of natural products used as pharmaceuticals, components of dietary supplements and cosmetics has increased tremendously requiring more extensive evaluation of their pharmacokinetic properties. PURPOSE: This study aims at combining in vitro and in silico methods to evaluate the gastrointestinal absorption (GIA) of natural flavonolignans from milk thistle (Silybum marianum (L.) Gaertn.) and their derivatives. METHODS: A parallel artificial membrane permeability assay (PAMPA) was used to evaluate the transcellular permeability of the plant main components. A dataset of 269 compounds with measured PAMPA values and specialized software tools for calculating molecular descriptors were utilized to develop a quantitative structure-activity relationship (QSAR) model to predict PAMPA permeability. RESULTS: The PAMPA permeabilities of 7 compounds constituting the main components of the milk thistle were measured and their GIA was evaluated. A freely-available and easy to use QSAR model predicting PAMPA permeability from calculated physico-chemical molecular descriptors was derived and validated on an external dataset of 783 compounds with known GIA. The predicted permeability values correlated well with obtained in vitro results. The QSAR model was further applied to predict the GIA of 31 experimentally untested flavonolignans. CONCLUSIONS: According to both in vitro and in silico results most flavonolignans are highly permeable in the gastrointestinal tract, which is a prerequisite for sufficient bioavailability and use as lead structures in drug development. The combined in vitro/in silico approach can be used for the preliminary evaluation of GIA and to guide further laboratory experiments on pharmacokinetic characterization of bioactive compounds, including natural products.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Flavonoides/química , Flavonoides/farmacocinética , Cardo-Mariano/química , Relação Quantitativa Estrutura-Atividade , Simulação por Computador , Suplementos Nutricionais , Flavonolignanos/farmacocinética , Humanos , Absorção Intestinal/efeitos dos fármacos , Membranas Artificiais
20.
J Nat Prod ; 81(12): 2630-2637, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30485098

RESUMO

1,4-Benzodioxane lignans are a class of bioactive compounds that have received much attention through the years. Herein research pertaining to both 1,4-benzodioxane flavonolignans and 1,4-benzodioxane neolignans is presented. A novel synthesis of both traditional 1,4-benzodioxane flavonolignans and 3-deoxyflavonolignans is described. The antiviral and cytotoxic activities of 1,4-benzodioxane neolignans were then investigated; eusiderins A, B, G, and M, deallyl eusiderin A, and nitidanin, which contain the 1,4-benzodioxane motif but lack the chromanone motif found in the known antiviral flavonolignans, were tested. Notably, it was found that all eusiderin 1,4-benzodioxane neolignans exhibited greater antiviral activity than the potent and well-known silybin flavonolignans. While most modifications of the C-1' side chain did not significantly alter the cytotoxicity or antiviral activity, eusiderin M and nitidanin, which contain an allylic alcohol side chain, had lower cytotoxicity. All the eusiderins had similar antiviral activities, with eusiderin B having the best selectivity index. These results show that the chromanone moiety of the flavonolignans is not essential for bioactivity.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Flavonolignanos/síntese química , Flavonolignanos/farmacologia , Lignanas/síntese química , Lignanas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Hepacivirus/efeitos dos fármacos , Humanos , Estrutura Molecular , Silibina/química
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