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1.
Food Chem ; 337: 127763, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791431

RESUMO

In this work, water-resistant poly (vinyl alcohol) (PVA)/poly (acrylic acid) (PAA) electrospun fibers encapsulating tangeretin (Tan) were fabricated by emulsion-electrospinning. To optimize the electrospinning condition, the size and morphology of electrospun fibers were characterized by dynamic light scattering (DLS), optical light microscope, fluorescence microscopy, and scanning electron microscopy (SEM), respectively. The optimized initial concentration of PVA/PAA was 10% (w/w) with a mass ratio of 3:7. The time and temperature of optimized thermal crosslinking treatment were 2 h and 145 °C, respectively. The results of XRD and SEM showed that the Tan was successfully incorporated into smooth PVA/PAA electrospun fibers and those fibers possessed nano-diameter size and high porosity. The encapsulation of Tan had no significant impact on the antioxidant activity of PVA/PAA/Tan crosslinking electrospun fibers. The in vitro release test showed the PVA/PAA/Tan crosslinking electrospun fibers achieved durable release profiles and lower burst release rates than that from the pure Tan emulsion. Based on these results, it is concluded that PVA/PAA/Tan crosslinking electrospun fibers prepared by emulsion-electrospinning serve as a promising technique in the fields of water-insoluble drug delivery and slow-release.


Assuntos
Resinas Acrílicas/química , Antioxidantes/química , Portadores de Fármacos/química , Eletricidade , Flavonas/química , Álcool de Polivinil/química , Liberação Controlada de Fármacos , Emulsões
2.
Chem Biol Interact ; 329: 109147, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32738202

RESUMO

Acacetin is a natural flavonoid that is widely distributed in plants and possesses numerous pharmacological activities. The aim of the present study was to investigate the effects of acacetin on the activities of the cytochrome P450 family members CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP2E1, and CYP3A2 in rat liver microsomes in vitro and rats in vivo to evaluate potential herb-drug interactions by using a cocktail approach. Phenacetin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and midazolam were chosen as the probe substrates. An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous detection of the probe substrates and their metabolites. In vitro, the mode of acacetin inhibition of CYP2B1, CYP2C11, and CYP2E1 was competitive, while mixed inhibition was observed for CYP1A2 and CYP3A2. The Ki values in this study were less than 8.32 µM. In vivo, the mixed probe substrates were administered by gavage after daily intraperitoneal injection with 50 mg/kg acacetin or saline for 2 weeks. The main pharmacokinetic parameters, area under the plasma concentration-time curve (AUC), plasma clearance (CL), and maximum plasma concentration (Cmax) of the probe substrates were significantly different in the experimental group than in the control group. Overall, the in vitro and in vivo results indicated that acacetin would be at high risk to cause toxicity and drug interactions via cytochrome P450 inhibition.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Flavonas/metabolismo , Animais , Área Sob a Curva , Sistema Enzimático do Citocromo P-450/química , Flavonas/química , Flavonas/farmacocinética , Meia-Vida , Concentração Inibidora 50 , Cinética , Masculino , Microssomos Hepáticos/metabolismo , Curva ROC , Ratos , Ratos Sprague-Dawley
3.
AAPS PharmSciTech ; 21(6): 226, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32761293

RESUMO

Approximately 40% of compounds in clinical drug development suffer from solubility and bioavailability challenges. Evidence from literature demonstrates the growing interest to utilize flavonoids as potential compounds owing to their widespread therapeutic utility in various ailments. Nobiletin (NOB), one such dietary polymethoxylated flavonoid found in citrus fruits, has multiple pharmacological effects such as antioxidant, anti-microbial, anti-cancer, and anti-inflammatory. It is useful in cancer, inflammatory bowel diseases, atherosclerosis, obesity, and Alzheimer's disease. Although preclinical studies demonstrate the therapeutic utility of NOB, it suffers from serious biopharmaceutical limitations such as low aqueous solubility (below 1 µg/ml), poor permeability across biological barriers, and low bioavailability. To overcome these biopharmaceutical challenges associated with NOB, the use of advanced formulations and nanotechnology-based strategies appears to be a promising approach to potentiate its therapeutic action. Multiple reviews cover the various therapeutic benefits of NOB in various diseases; however, there is an absence of a comprehensive review that focuses on the formulation development strategies of NOB. The purpose of this review is to provide a concise perspective on NOB as a candidate molecule for formulation development. The manuscript covers various aspects related to NOB, such as its chemistry, physicochemical properties, and pharmacological effects. This is also a thorough review of various formulation development strategies with advances made in the past years to improve the solubility, bioavailability, and therapeutic efficacy of NOB. The review also contains information related to toxicity and patents involving NOB and its formulation.


Assuntos
Antioxidantes/química , Composição de Medicamentos , Flavonas/química , Nanotecnologia , Animais , Antioxidantes/farmacocinética , Disponibilidade Biológica , Flavonas/farmacocinética , Humanos , Solubilidade
4.
Chem Biol Interact ; 325: 109109, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32376239

RESUMO

A series of 10 natural and semisynthetic flavonoids (1 to 10) were obtained from Gardenia oudiepe (Rubiaceae), an endemic plant from New Caledonia. Most of them were polymethoxylated flavones (PMFs) of rare occurrence. After a cell viability screening test, PMFs 2 and 3 showed significant cytotoxic activity against A2058 human melanoma cells (IC50 = 3.92 and 8.18 µM, respectively) and were selected for in-depth pharmacological assays. Both compounds inhibited cell migration and induced apoptosis and cell cycle arrest after 72h of treatment. Immunofluorescence assays indicated that these outcomes were possibly related to the induction of cytoskeleton disruption associated to actin and tubulin depolymerization. These data were confirmed by molecular docking studies, which showed a good interaction between PMFs 2 and 3 and tubulin, particularly at the colchicine binding site. As A2058 are considered as chemoresistant to conventional chemotherapy, compounds 2 and 3 (½IC50) were associated to clinically-used antimelanoma drugs (vemurafenib and dacarbazine) and combined therapies efficacy was assessed by the MTT assay. PMFs 2 restored the sensitivity of A2058 cells to dacarbazine treatment (IC50 = 49.38 µM vs. >100 µM). Taken together, these data suggest that PMFs from G. oudiepe could be potential leaders for the design of new antimelanoma drugs.


Assuntos
Apoptose/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Flavonas/farmacologia , Gardenia/química , Melanoma/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citoesqueleto/metabolismo , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Flavonas/química , Flavonas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
5.
Biomed J ; 43(4): 363-367, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32426388

RESUMO

Background: The present study demonstrates the potential of flavanoid narcissoside against the novel corona virus (COVID-19) complications using molecular docking studies. Methods: The computation molecular docking screening was performed using Molegro Virtual Docker software (MVD) with grid resolution of 30 Å. Protein of COVID 19 virus was taken from protein data bank. Results: The standard inhibitor X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide) identified from the protein inhibitor complex 6W63 from protein data bank was docked with COVID 19 protein 6W63 which showed MolDock score of -156.913, rerank Sore -121.296 and H Bond -5.7369, while the flavanoid narcissoside had showed MolDock score -180.739, Rerank Sore -137.092 and H Bond -18.6771. The narcissoside showed potent inhibitory effect which is greater than standard X77. The result showed that narcissoside have high affinity towards 6W63 as it showed thirteen hydrogen bonds with nine amino acids (Arg 188, Glu 166, His 164, Cys 145 (2 bonds), Asn 14 (2 bonds), Cys 44 (2 bonds), His 41 (2 bonds), Gln 192, Thr 190) while X777 showed four hydrogen bonds with amino acids (Gly 143, Cys 145, Glu 166, Ser 144). Conclusion: From computation approach it was concluded that narcissoside is a potent inhibitor of viral COVID 19 protein 6W63. The narcissoside have high affinity and inhibition potential than standard inhibitor X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide). The narcissoside predicted as more potent inhibitor which can be further optimize, pharmacologically and clinically evaluated for the treatment of novel coronavirus COVID-19.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Flavonas/farmacologia , Simulação de Acoplamento Molecular , Pneumonia Viral/tratamento farmacológico , Flavonas/química , Humanos , Simulação de Acoplamento Molecular/métodos , Pandemias , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia
6.
Food Chem ; 324: 126871, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32344346

RESUMO

Flavones are important bioactive flavonoids in cereal grains, but are poorly characterized. This study investigated rye flavone profile as influenced by phenotype (grain color), sourdough fermentation, and subsequent heat processing. Twelve rye varieties belonging to 4 phenotypes were characterized using UPLC-tandem quadrupole MS before and after fermentation and baking. Antioxidant properties were also assessed. Rye flavones (range 57-137 µg/g) were dominated by O-glycosides (50-68%), present as derivatives of tricin (exclusively O-glycosides), chrysoeriol (O-/C-glycosides), and apigenin (exclusively C-glycosides). Phenotype did not influence flavone content. Fermentation partially hydrolyzed O-glycosides to their aglycones, but did not affect C-glycosides. Extractable phenols and antioxidants increased 1.9-3.6X after 96-h fermentation; baking further increased these components by 36-96% in fermented samples, likely via enhanced cell wall disruption. The high proportion of flavone-O-glycosides in rye is of interest due to their known higher bioavailability relative to typical cereal grain C-glycosides.


Assuntos
Antioxidantes/química , Flavonas/química , Flavonoides/química , Secale/química , Cromatografia Líquida de Alta Pressão , Flavonas/análise , Flavonoides/análise , Glicosídeos/análise , Glicosídeos/química , Temperatura Alta , Espectrometria de Massas , Fenóis/análise , Fenóis/química , Secale/metabolismo
7.
Mol Biol (Mosk) ; 54(1): 153-163, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32163399

RESUMO

Antibiotic resistance is a global problem nowadays and in 2017 the World Health Organization published the list of bacteria for which treatment are urgently needed, where Pseudomonas aeruginosa is of critical priority. Current therapies lack efficacy because this organism creates biofilms conferring increased resistance to antibiotics and host immune responses. The strategy is to "not kill, but disarm" the pathogen and resistance will be developed slowly. It has been shown that LasI/LasR system is the main component of the quorum sensing system in P. aeruginosa. LasR is activated by the interaction with its native autoinducer. A lot flavones and their derivatives are used as antibacterial drug compounds. The purpose is to search compounds that will inhibit LasR. This leads to the inhibition of the synthesis of virulence factors thus the bacteria will be vulnerable and not virulent. We performed virtual screening using AutoDock Vina, rDock, LeDock for obtaining consensus predictions. The results of virtual screening suggest benzamides which are synthetical derivatives of flavones as potential inhibitors of transcriptional regulator LasR. These are consistent with recently published experimental data, which demonstrate the high antibacterial activity of benzamides. The compounds interact with the ligand binding domain of LasR with higher binding affinity than with DNA binding domain. Among the selected compounds, by conformational analysis, it was found that there are compounds that bind to the same amino acids of ligand binding domain as the native autoinducer. This could indicate the possibility of competitive interaction of these compounds. A number of compounds that bind to other conservative amino acids ligand binding domain have also been discovered, which will be of interest for further study. Selected compounds meet the criteria necessary for their consideration as drugs and can serve as a basis for conducting further in vitro/in vivo experiments. It could be used for the development of modern anti-infective therapy based on the quorum sensing system of P. aeruginosa.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Simulação por Computador , Flavonas/química , Flavonas/farmacologia , Pseudomonas aeruginosa , Percepção de Quorum/efeitos dos fármacos , Transativadores/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos
8.
Asian Pac J Cancer Prev ; 21(3): 611-620, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32212785

RESUMO

OBJECTIVE: Nobiletin treatment on MDA-MB 231 cells reduces the expression of CXC chemokine receptor type 4 (CXCR4), which is highly expressed in cancer stem cell populations in tumor patients. However, the mechanisms of nobiletin in cancer stem cells (CSCs) remain elusive. This study was aimed to explore the potential target and mechanisms of nobiletin in cancer stem cells using bioinformatics approaches. METHODS: Gene expression profiles by public COMPARE predicting the sensitivity of tumor cells to nobiletin. Functional annotations on gene lists are carried out with The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8, and WEB-based GEne SeT Analysis Toolkit (WebGestalt). The protein-protein interaction (PPI) network was analyzed by STRING-DB and visualized by Cytoscape. RESULTS: Microarray analyses reveal many genes involved in protein binding, transcriptional and translational activity. Pathway enrichment analysis revealed breast cancer regulation of estrogen signaling and Wnt/ß-catenin by nobiletin. Moreover, three hub genes, i.e. ESR1, NCOA3, and RPS6KB1 and one significant module were filtered out and selected from the PPI network. CONCLUSION: Nobiletin might serve as a lead compound for the development of CSCs-targeted drugs by targeting estrogen and Wnt/ß-catenin signaling. Further studies are needed to explore the full therapeutic potential of nobiletin in cancer stem cells.
.


Assuntos
Flavonas/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Linhagem Celular Tumoral , Biologia Computacional , Flavonas/química , Humanos , Células-Tronco Neoplásicas/metabolismo , RNA Mensageiro/genética , Transdução de Sinais/efeitos dos fármacos
9.
Molecules ; 25(4)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32075249

RESUMO

O-methylation of flavonoids is an important modification reaction that occurs in plants. O-methylation contributes to the structural diversity of flavonoids, which have several biological and pharmacological functions. In this study, an O-methyltransferase gene (CrOMT2) was isolated from the fruit peel of Citrus reticulata, which encoding a multifunctional O-methyltransferase and could effectively catalyze the methylation of 3'-, 5'-, and 7-OH of flavonoids with vicinal hydroxyl substitutions. Substrate preference assays indicated that this recombinant enzyme favored polymethoxylated flavones (PMF)-type substrates in vitro, thereby providing biochemical evidence for the potential role of the enzyme in plants. Additionally, the cytotoxicity of the methylated products from the enzymatic catalytic reaction was evaluated in vitro using human gastric cell lines SGC-7901 and BGC-823. The results showed that the in vitro cytotoxicity of the flavonoids with the unsaturated C2-C3 bond was increased after being methylated at position 3'. These combined results provide biochemical insight regarding CrOMT2 in vitro and indicate the in vitro cytotoxicity of the products methylated by its catalytic reaction.


Assuntos
Citrus/enzimologia , Citotoxinas/farmacologia , Flavonas/farmacologia , Proteínas de Plantas/química , Proteína O-Metiltransferase/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citrus/química , Citotoxinas/química , Citotoxinas/isolamento & purificação , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Flavonas/química , Flavonas/isolamento & purificação , Frutas/química , Frutas/enzimologia , Humanos , Concentração Inibidora 50 , Metilação , Proteínas de Plantas/isolamento & purificação , Proteína O-Metiltransferase/isolamento & purificação , Especificidade por Substrato
10.
Food Chem ; 317: 126229, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32078989

RESUMO

The impact of nanoemulsions containing triglycerides with different fatty acid chain lengths on the bioavailability of a highly lipophilic bioactive: 5-demethylnobiletin (5-DN) was investigated. 5-DN was encapsulated in nanoemulsions fabricated using either medium-chain triglycerides (MCT) or long-chain triglycerides (LCT). They were then subjected to in vitro digestion, and the resulting mixed micelles was applied to a Caco-2 cell model. Higher 5-DN bioaccessibility was found for the MCT-nanoemulsion (13%) than for the LCT-nanoemulsion (7%). However, only 30% 5-DN in MCT crossed the Caco-2 monolayer and 50% was metabolized, while 60% 5-DN in LCT crossed the monolayer and only 10% was metabolized. More lipid droplets and chylomicrons were also formed for the LCT nanoemulsions, indicating greater 5-DN transported through lymph. Although MCT gave a higher 5-DN bioaccessibility, the final amount of 5-DN absorbed and transported to the lymph was inferior to that of the LCT formulation.


Assuntos
Micelas , Nanoestruturas/química , Triglicerídeos/química , Células CACO-2 , Quilomícrons/metabolismo , Flavonas/química , Flavonas/metabolismo , Humanos , Gotículas Lipídicas/metabolismo , Modelos Biológicos , Tamanho da Partícula , Triglicerídeos/metabolismo
11.
Food Funct ; 11(2): 1810-1825, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32057043

RESUMO

Anti-solvent co-precipitation (ASCP) is the most commonly used method of fabricating food-grade nanoparticles, while the impact of the blending sequence on the formation of nanoparticles lacks research. In this study, 7,8-dihydroxyflavone (7,8-DHF) loaded zein-/sophorolipid nanoparticles with two blending sequences (DHF-Z-S and DHF-Z/S) were successfully fabricated by the ASCP method and used to improve the storage stability and the in vitro bioaccessibility of 7,8-DHF. The results showed that blending sequences significantly affect the physicochemical properties of nanoparticles. DHF-Z-S nanoparticles had smaller particle size, lower polydispersity index and turbidity, and higher negative charge, entrapment efficiency and loading capacity compared to DHF-Z/S nanoparticles. Transmission electron microscopy and scanning electron microscopy revealed that DHF-Z-S and DHF-Z/S nanoparticles have core-shell spherical shape at the nanoscale and sophorolipid changed the surface morphology of zein nanoparticles. Fourier transform infrared spectroscopy and fluorescence spectrum analysis confirmed the presence of effective hydrogen bonding, electrostatic interactions and hydrophobic effects between 7,8-DHF, zein and sophorolipid and the presence of stronger hydrogen bonding and hydrophobic effects in DHF-Z-S nanoparticles. The encapsulated 7,8-DHF was in an amorphous state rather than a crystalline form as determined by X-ray diffraction analysis. Circular dichroism revealed that 7,8-DHF and sophorolipid were capable of changing the secondary structure of zein remarkably. More importantly, compared to DHF-Z/S nanoparticles, the DHF-Z-S nanoparticles possessed higher storage stability and in vitro bioaccessibility. Collectively, DHF-Z-S nanoparticles developed in this study might be a promising means of encapsulating, protecting and delivering hydrophobic nutraceuticals for applications in functional foods.


Assuntos
Flavonas , Nanopartículas/química , Ácidos Oleicos/química , Zeína/química , Composição de Medicamentos , Flavonas/química , Flavonas/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Modelos Biológicos , Concentração Osmolar , Tamanho da Partícula
12.
Sci Rep ; 10(1): 599, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953434

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder caused due to loss of dopaminergic neurons in substantia nigra pars compacta, which occurs the presence of Lewy bodies made up of Alpha-synuclein (ASN) aggregation resulting in neuronal death. This study aims to identify potent 7,8-Dihydroxyflavone (DHF) derivatives to inhibit the ASN aggregation from in silico analysis. Molecular docking study reveals that carbamic ester derivatives of DHF [DHF-BAHPC (8q), DHF-BAHPEC (8s), DHF-BAHEC (8p), DHF-BDOPC (8c), DHF-BAPEC (8n) and DHF-BAMC (8h)] have good binding affinity towards ASN, when compared with DHF and L-DOPA; their docking score values are -16.3120, -16.1875, -15.2223, -14.3118, -14.2893, -14.2810, -14.0383, and -9.1560 kcal/mol respectively. The in silico pharmacological evaluation shows that these molecules exhibit the drug-likeness and ADMET properties. Molecular dynamics simulation confirms the stability of the molecules with ASN. The intermolecular interaction analyzed under the dynamic condition, allows to identify the candidate which potentially inhibits ASN aggregation. Hence, we propose that DHF derivatives are the potential lead drug molecules and preclinical studies are needed to confirm the promising therapeutic ability against PD.


Assuntos
Carbamatos/síntese química , Ésteres/síntese química , Flavonas/química , alfa-Sinucleína/antagonistas & inibidores , Carbamatos/química , Carbamatos/farmacologia , Simulação por Computador , Desenho de Fármacos , Ésteres/química , Ésteres/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , alfa-Sinucleína/química
13.
Int J Biol Macromol ; 146: 179-192, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899246

RESUMO

7,8-dihydroxyflavone (7,8-DHF), a tyrosine kinase B (TrkB) receptor agonist, can mimick physiological actions of brain-derived neurotrophic factor (BDNF) to attenuate neurogenic disease. However, its use as a functional food, is limited by its low-water solubility, chemical instability, and poor bioavailability. The purpose of this work is to fabricate stable 7,8-DHF loaded zein/lactoferrin (LF) composite nanoparticles (zein/LF-DHF) to overcome these challenges. Results showed that mean particle size of zein/LF nanoparticles was about 74 nm with low polydispersity index (<0.200) and turbidity (<0.300) values. Zein/LF nanoparticles had good stability against pH (3.0-9.0), ionic strengths (0-500 mM NaCl at neutral pH) and long-term storage. Zein/LF nanoparticles showed spherical structures formed by hydrogen bonding and hydrophobic interactions, however, LF changed surface morphology of zein nanoparticles as observed by scanning electron microscope. X-ray diffraction indicated 7,8-DHF was presented in an amorphous state inside zein/LF nanoparticles. Most importantly, zein/LF-DHF had good redispersibility, and increased the encapsulation efficiency, chemical stability, water solubility and bioaccessibility of 7,8-DHF. Collectively, zein/LF nanoparticles are promising delivery systems for 7,8-DHF in functional foods.


Assuntos
Flavonas/química , Lactoferrina/química , Nanopartículas/química , Zeína/química , Concentração de Íons de Hidrogênio
14.
Int J Mol Sci ; 21(1)2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31948007

RESUMO

Nobiletin (NOB), one of polymethoxyflavone existing in citrus fruits, has been reported to exhibit a multitude of biological properties, including anti-inflammation, anti-oxidation, anti-atherosclerosis, neuroprotection, and anti-tumor activity. However, little is known about the anti-aging effect of NOB. The objective of this study was to determine the effects of NOB on lifespan, stress resistance, and its associated gene expression. Using Caenorhabditis elegans, an in vivo nematode model, we found that NOB remarkably extended the lifespan; slowed aging-related functional declines; and increased the resistance against various stressors, including heat shock and ultraviolet radiation. Also, NOB reduced the effects of paraquat stressor on nematodes and scavenged reactive oxygen species (ROS). Furthermore, gene expression revealed that NOB upregulated the expression of sod-3, hsp-16.2, gst-4, skn-1, sek-1, and sir-2.1, which was suggested that anti-aging activity of NOB was mediated most likely by activation of the target genes of the transcription factors including dauer formation (DAF)-16, heat-shock transcription factor (HSF)-1, and skinhead (SKN)-1. In summary, NOB has potential application in extension of lifespan, and its associated healthspan and stress resistances.


Assuntos
Caenorhabditis elegans/metabolismo , Flavonas/farmacologia , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Citrus/química , Citrus/metabolismo , Flavonas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Lipofuscina/metabolismo , Longevidade/efeitos da radiação , Estresse Oxidativo/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Reprodução/efeitos dos fármacos , Temperatura , Raios Ultravioleta
15.
Sci Adv ; 6(1): eaax6208, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31922003

RESUMO

Metabolic syndrome (MetS) is intricately linked to dysregulation of gut microbiota and host metabolomes. Here, we first find that a purified citrus polymethoxyflavone-rich extract (PMFE) potently ameliorates high-fat diet (HFD)-induced MetS, alleviates gut dysbiosis, and regulates branched-chain amino acid (BCAA) metabolism using 16S rDNA amplicon sequencing and metabolomic profiling. The metabolic protective effects of PMFE are gut microbiota dependent, as demonstrated by antibiotic treatment and fecal microbiome transplantation (FMT). The modulation of gut microbiota altered BCAA levels in the host serum and feces, which were significantly associated with metabolic features and actively responsive to therapeutic interventions with PMFE. Notably, PMFE greatly enriched the commensal bacterium Bacteroides ovatus, and gavage with B. ovatus reduced BCAA concentrations and alleviated MetS in HFD mice. PMFE may be used as a prebiotic agent to attenuate MetS, and target-specific microbial species may have unique therapeutic promise for metabolic diseases.


Assuntos
Flavonas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Aminoácidos/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Citrus/química , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Disbiose/patologia , Fezes/microbiologia , Flavonas/química , Humanos , Resistência à Insulina/genética , Síndrome Metabólica/microbiologia , Síndrome Metabólica/patologia , Metaboloma/efeitos dos fármacos , Camundongos , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/patologia , Prebióticos/microbiologia
16.
Food Chem ; 310: 125734, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31791725

RESUMO

Anthocyanins are a major source of natural red colorants but currently face difficulties matching the hue range, stability, and affordability of synthetic options. Purple corn offers an FDA and EFSA-approved economical source of anthocyanin-based colorants. A C-glycosyl flavone and anthocyanin copigmentation system consisting of a flavone-rich anthocyanin-poor line and two anthocyanin-rich flavone-poor lines containing either pelargonidin or cyanidin-derived anthocyanins is described. This system offers a broad hue range and can improve stability. Cyanidin-rich model beverages had better stability than pelargonidin-rich beverages over time, but the addition of flavone-rich extract to both resulted in significantly longer half-lives (up to 50% longer). Flavone copigments produced hyperchromic and bathochromic shifts in both. A protective effect from flavone copigmentation was observed for glycosides. In contrast acylated forms displayed significantly shorter half-lives. Results suggest that corn C-glycosyl flavone-rich extracts could serve as a color enhancing and stabilizing agent for anthocyanin colorants.


Assuntos
Antocianinas/química , Flavonas/química , Corantes de Alimentos/química , Extratos Vegetais/química , Zea mays/química , Antocianinas/análise , Bebidas , Flavonas/análise , Pigmentos Biológicos/química
17.
J Agric Food Chem ; 68(1): 97-105, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31830779

RESUMO

The oral delivery efficiency of aged citrus peel extract containing polymethoxyflavones and 5-demethylated polymethoxyflavones (PMFs) in three different systems, including a pure oil phase, a Tween 80-stabilized nanoemulsion, and a milled-cellulose-particles-stabilized Pickering emulsion, was investigated using two typical in vitro digestion models. The digestion profiles and release of PMFs in these emulsions and bulk oil in the human upper gastrointestinal (GI) tract were evaluated using the pH-stat lipolysis model and TNO's gastrointestinal model (TIM-1). Compared to the bulk oil sample, the bioaccessibilities of PMFs in the nanoemulsion and Pickering emulsion were both increased by around 14 fold when the pH-stat lipolysis model was used. However, the results from the TIM-1 system indicated that the bioaccessibilities of PMFs in the nanoemulsion and Pickering emulsion were around two and four times that in bulk oil, respectively. The results from this work would provide valuable information for the rational design and evaluation of lipid-based delivery systems for lipophilic bioactive compounds.


Assuntos
Citrus/metabolismo , Composição de Medicamentos/métodos , Lipídeos/química , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Citrus/química , Digestão , Emulsões/química , Flavonas/química , Flavonas/metabolismo , Frutas/química , Frutas/metabolismo , Trato Gastrointestinal , Humanos , Modelos Biológicos , Tamanho da Partícula
18.
Eur J Med Chem ; 187: 111965, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31877541

RESUMO

Several arylamide-based antiproliferative agents are known and some of them are currently FDA-approved anticancer drugs. Provoked by the need to fill the existing room with new drugs, 31 compounds constituting a series of flavone-based arylamide derivatives were synthesized and biologically evaluated. Towards extensive evaluation, sixty diverse cancer cell lines representing nine cancer diseases of various origins have been used for evaluation of their efficacy, spectrum and potency. Two compounds 2aw and 2ax emerged as effective, broad-spectrum and potent anticancer agents that outperformed masitinibt and imatininb, which are FDA-approved anticancer drugs. Kinases profiling as possible targets for the potent compound 2aw showed that it might be a hit compound offering a starting point to develop inhibitors of STE20/GCK-IV kinase family members including HGK, TNIK and MINK1 kinases. Mechanistic study showed that compounds 2aw triggers cell cycle arrest in HT29 colon cancer cells. In conclusion, this work presents compound 2aw as a new broad-spectrum anticancer agent for further development of promising treatment of diverse cancers.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Flavonas/farmacologia , Amidas/síntese química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flavonas/química , Células HT29 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
19.
Toxicol In Vitro ; 62: 104681, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31655123

RESUMO

Cytochrome P4501A1 (CYP1A1) is involved in the metabolism of several genotoxic/carcinogenic environmental xenobiotics including polycyclic aromatic hydrocarbons (PAHs) like benzo[a]pyrene. Several authors had proposed CYP1A inhibition as a plausible strategy for cancer chemoprevention. Using ethoxyresorufin O-deethylase activity (EROD), we tested the inhibitory properties of nine flavonoids: quercetin, miricetin, luteolin, fisetin, morin, kaempferol, 5-hydroxyflavone (5-HF), 3-hydroxyflavone (3-HF), and flavone (F) against human recombinant CYP1A1. The last three compounds exerted the highest inhibitory effect with IC50 values of 0.07, 0.10 and 0.08 µM respectively; the more hydroxyl-groups were present, the lower the potency of inhibition was. Biochemical characterization leads to the conclusion that flavone and its hydroxy derivatives are mixed-type inhibitors. In silico studies have shown that, Phe224 and other aromatic residues in the human CYP1A1 active site play an important role in flavonoid-CYP interaction, through a π/π stacking between the aminoacid and the flavonoid C-ring. Outside the active site, the three flavonoids bind preferentially between A and K helices of the enzyme. Results from the Ames test using human S9 fraction revealed that none of the three compounds was mutagenic. We can consider 5-HF, 3-HF, and F as potential chemopreventive agents against genotoxic damage caused by metabolites resulting from CYP1A1 activity.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Citocromo P-450 CYP1A1/antagonistas & inibidores , Flavonoides/farmacologia , Aminoácidos/metabolismo , Antimutagênicos/farmacologia , Simulação por Computador , Flavonas/química , Flavonas/farmacologia , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Testes de Mutagenicidade , Mutagênicos/farmacologia , Proteínas Recombinantes , Relação Estrutura-Atividade
20.
Zhongguo Zhong Yao Za Zhi ; 44(22): 4880-4887, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31872596

RESUMO

The tandem mass spectrum of apigenin-6,8-C-di-glucoside( 1) and apigenin-6-C-glucose-8-C-rhamnoside( 2) were obtained by high resolution electrospray ionization mass spectrometry( HR-ESI-MS/MS) in both positive and negative ion modes. The elemental composition of each ion was determined according to its accurate mass-to-charge,hence,the fragmentation pathways of each compound were proposed in both negative and positive ion modes. Comprehensive analysis of each ion and its proposed fragmentation pathways of the two compounds was initially conducted in both negative and positive ion mode HR-ESI-MS/MS to explore the diagnostic ions for flavone-6,8-C-di-glycosides and the characteristic ions for each compound and their cleavage rules. The results showed that a family of fragmentation ions with m/z 353,325,311,297 in ESI(-)-MS and m/z 355,325,307,295 in ESI( +)-MS could be the diagnostic ions of flavone-6,8-C-di-glycoside,and characteristic neutral loss could be assigned to glycosyl substitution,for example,neutral losses of C_4H_8O_4( 120),C_3H_6O_3( 90),C_2H_4O_2( 60) for glucoside substitution while neutral losses of C_4H_8O_3(104),C_3H_6O_2( 74),C_2H_4O( 44) for rhamnoside substitution. Furthermore,only one H_2O loss from mother ion( [M-H]-) was observed for 1 & 2 in ESI(-)-MS while five to six H2 O loss from mother ion( [M+H]+) was observed for 1 & 2 in ESI( +)-MS to produce a family of ions by subsequent loss of H_2O,which could be applied for glucosyl difference. The flavone-6,8-C-di-glycosides in both ESI( +)-MS and ESI(-)-MS showed the cleavage similarity at sugar substitutions. However,there were much more differences by the fragmentation pathways and neutral losses between ESI( +)-MS and ESI(-)-MS as following,hyperconjugation ions by subsequent loss of H_2O from precursor ions of flavone-6,8-C-di-glycosides in ESI( +)-MS were not observed in ESI(-)-MS; the subsequent neutral loss of CH_2O in ESI( +)-MS were rarely observed in ESI(-)-MS; the loss of CO only happen at C-ring of flavone ESI( +)-MS other than glycosyl position in ESI(-)-MS; the C4-chain neutral loss of flavone-6,8-C-di-glycosides happened at 8-C-glycosyl position other than at 6-C-glycosyl position. The above cleavage rules and diagnostic ions of ESI( +)-MS were successfully applied for the structure identification of 4 flavone-6 C,8 C-diglycosides from the stem extract of Dendrobium officinale as vicenin Ⅱ,vicenin Ⅰ,isoschaftoside,schaftoside as well as one flavone-O-glysoside named rutin,which were supported by ESI(-)-MS data as well.


Assuntos
Flavonas/química , Glicosídeos/química , Íons , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
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