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1.
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
2.
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
3.
Int J Nanomedicine ; 14: 7839-7849, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576127

RESUMO

Background: Nobiletin (NOB), a polymethoxy flavonoid, possesses anti-cancer and anti-inflammatory activities, has been reported that it played role in anti-osteoporosis treatment. However, previous research did not focus on practical use due to lack of hydrophilicity and cytotoxicity at high concentrations. The aim of this study was to develop a therapeutic formulation for osteoporosis based on the utilization of NOB. Methods: In this study, NOB-loaded poly(ethylene glycol)-block-poly(e-caprolactone) (NOB-PEG-PCL) was prepared by dialysis method. The effects on osteoclasts and anti-osteoporosis functions were investigated in a RANKL-induced cell model and ovariectomized (OVX) mice. Results: Dynamic light scattering and transmission electron microscopy examination results revealed that the NOB-PEG-PCL had a round shape, with a mean diameter around 124 nm. The encapsulation efficiency and drug loading were 76.34±3.25% and 7.60±0.48%, respectively. The in vitro release of NOB from NOB-PEG-PCL showed a remarkably sustained releasing characteristic and could be retained at least 48 hrs in pH 7.4 PBS. Anti-osteoclasts effects demonstrated that the NOB-PEG-PCL significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells stimulated by RANKL. Furthermore, the NOB-PEG-PCL did not produce cytotoxicity on bone marrow-derived macrophages (BMMs). The mRNA expressions of genetic markers of osteoclasts including TRAP and cathepsin K were significantly decreased in the presence of NOB-PEG-PCL. In addition, the NOB-PEG-PCL inhibited OC differentiation of BMMs through RANKL-induced MAPK signal pathway. After administration of the NOB-PEG-PCL, NOB-PEG-PCL prevented bone loss and improved bone density in OVX mice. These findings suggest that NOB-PEG-PCL might have great potential in the treatment of osteoporosis. Conclusion: The results suggested that NOB-PEG-PCL micelles could effectively prevent NOB fast release from micelles and extend circulation time. The NOB-PEG-PCL delivery system may be a promising way to prevent and treat osteoporosis.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Flavonas/uso terapêutico , Micelas , Osteoclastos/patologia , Osteogênese , Ovariectomia/efeitos adversos , Animais , Morte Celular/efeitos dos fármacos , Citocinas/metabolismo , Liberação Controlada de Fármacos , Feminino , Flavonas/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Poliésteres/química , Polietilenoglicóis/química , Transdução de Sinais/efeitos dos fármacos
4.
J Chromatogr Sci ; 57(9): 838-846, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31504273

RESUMO

There is an increasing interest in screening and developing natural tyrosinase inhibitors widely applied in medicinal and cosmetic products, as well as in the food industry. In this study, an approach by ultrafiltration LC-MS and molecular docking was used to screen and identify tyrosinase inhibitors from Semen Oroxyli extract. The samples were first incubated with the tyrosinase to select the optimal binding conditions including tyrosinase concentration, incubation time and the molecular weight of ultrafiltration membrane. By comparison of the chromatographic profiles of the extracts after ultrafiltration with activated and inactivated tyrosinase, the potential inhibitors were obtained and then identified by LC-MS. The relative binding affinities of the potential inhibitors were also calculated based on the decrease of peak areas of those. As a result, seven compounds were fished out as tyrosinase inhibitors by this assay. Among them, oroxin A and baicalein showed higher tyrosinase inhibitory than resveratrol as positive drug, and their binding mode with enzyme was further verified via the molecular docking analysis. The test results showed that the proposed method was a simple, rapid, effective, and reliable method for the discovery of natural bioactive compounds, and it can be extended to screen other bioactive compounds from traditional Chinese medicines.


Assuntos
Bignoniaceae , Descoberta de Drogas/métodos , Inibidores Enzimáticos , Monofenol Mono-Oxigenase/antagonistas & inibidores , Extratos Vegetais , Cromatografia Líquida de Alta Pressão/métodos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Flavonas/análise , Flavonas/química , Flavonas/metabolismo , Glucosídeos/análise , Glucosídeos/química , Glucosídeos/metabolismo , Espectrometria de Massas/métodos , Simulação de Acoplamento Molecular/métodos , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/metabolismo , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Ultrafiltração/métodos
5.
Chem Pharm Bull (Tokyo) ; 67(9): 935-939, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474732

RESUMO

Chafuroside A and chafuroside B are flavone C-glycosides isolated from oolong tea leaves. They have a number of beneficial pharmacological activities related to antiinflammation at various concentrations. However, no crystallographic study of chafurosides has yet been reported. In the present study, the crystal structures of chafuroside A and chafuroside B were investigated using single-crystal X-ray diffraction. The asymmetric unit of the chafuroside A crystal consists of one chafuroside A and two water molecules, and that of chafuroside B contains one chafuroside B and one water molecule. The flavone moiety of chafuroside A is curved, i.e., the angle between the best-fit planes of the chromene and phenyl rings is 18.9°, whereas the chafuroside B flavone moiety is relatively flat. A comparison of the curvatures of the flavone moieties of various C-glycosides showed that the curvature of chafuroside A is significantly larger than those of the others. This structural feature might contribute to the differences between the strengths of the pharmacological activities of chafurosides A and B.


Assuntos
Flavonas/química , Glicosídeos/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Chá/química , Camellia sinensis/química , Camellia sinensis/metabolismo , Cristalografia por Raios X , Conformação Molecular , Folhas de Planta/química , Folhas de Planta/metabolismo
6.
J Agric Food Chem ; 67(36): 10222-10234, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31385700

RESUMO

The emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) critically requires alternative therapeutic options. New antibacterial drugs and strategies are urgently needed to combat MRSA-associated infections. Here, we investigated the antibacterial activity of flavones from Morus alba and the potential mode of action against MRSA. Kuwanon G, kuwanon H, mulberrin, and morusin displayed high efficiency in killing diverse MRSA isolates. On the basis of structure-activity analysis, the cyclohexene-phenyl ketones and isopentenyl groups were critical to increase the membrane permeability and to dissipate the proton motive force. Meanwhile, mechanistic studies further showed that kuwanon G displayed rapid bactericidal activity in vitrowith difficulty in developing drug resistance. Kuwanon G targeted phosphatidylglycerol and cardiolipin in the cytoplasmic membrane through the formation of hydrogen bonds and electrostatic interactions. Additionally, kuwanon G promoted wound healing in a mouse model of MRSA skin infection. In summary, these results indicate that flavones are promising lead compounds to treat MRSA-associated infections through disrupting the proton motive force and membrane permeability.


Assuntos
Antibacterianos/farmacologia , Flavonas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Morus/química , Extratos Vegetais/farmacologia , Infecções Estafilocócicas/microbiologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Permeabilidade da Membrana Celular/efeitos dos fármacos , Feminino , Flavonas/química , Flavonas/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Humanos , Masculino , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/genética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Raízes de Plantas/química , Força Próton-Motriz/efeitos dos fármacos
7.
Molecules ; 24(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336931

RESUMO

The abnormal regulation of melanin synthesis leads to a wide range of pigmentary disorders. Although various melanin biosynthesis inhibitors have been developed, their efficacy and long-term safety needs to be further improved, and thus the goal of this study is to develop promising natural compound inhibitors of melanin biosynthesis. Here, we obtained aglycone flavonoid extract through the microwave-assisted hydrolysis of glycoside extract from Korean mistletoe in acidic condition. The aglycone extract inhibited tyrosinase activity more efficiently with better antioxidant activity than glycoside extract in vitro. The microwave-assisted aglycone extract of mistletoe was further analyzed for in vivo activity, and the results showed the aglycone extract inhibited both early melanocyte development and melanin synthesis more efficiently in zebrafish embryo in a dose-dependent manner. Our in vivo toxicity assay quantitatively measured cell death in zebrafish embryos and showed that the microwave-assisted aglycone extract of mistletoe had no significant effect on cell death (p < 0.001), indicating that aglycone extract is more biocompatible than glycoside extract. Furthermore, our in vitro and in vivo analyses successfully identified and characterized velutin, an aglycone of a homoflavoyadorinin B glycoside, as a major inhibitory component in the microwave-assisted mistletoe extract. Ultimately, this study showed that the novel natural compound inhibitor velutin, which was generated through microwave-assisted extraction from mistletoe, improved the efficacy of melanin biosynthesis inhibition with little toxicity.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Flavonas/farmacologia , Melaninas/biossíntese , Erva-de-Passarinho/química , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Fracionamento Químico , Cromatografia Líquida de Alta Pressão , Flavonas/química , Flavonas/isolamento & purificação , Flavonoides/química , Flavonoides/farmacologia , Glicosídeos/química , Hidrólise , Melanócitos/metabolismo , Micro-Ondas , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Peixe-Zebra
8.
Molecules ; 24(14)2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337014

RESUMO

Ochratoxin A (OTA) is a mycotoxin with a serious impact on human health. In Mediterranean countries, the black Aspergilli group, in particular Aspergillus carbonarius, causes the highest OTA contamination. Here we describe the synthesis of three polyphenolic flavonoids: 5-hydroxy-6,7-dimethoxy-flavone (MOS), 5,6-dihydroxy-7-methoxy-flavone (NEG), and 5,6 dihydroxy-flavone (DHF), as well as their effect on the prevention of OTA biosynthesis and lipoxygenase (LOX) activity in A. carbonarius cultured in a conducive liquid medium. The best control effect on OTA biosynthesis was achieved using NEG and DHF. In fungal cultures treated with these compounds at 5, 25, and 50 µg/mL, OTA biosynthesis significantly decreased throughout the 8-day experiment. NEG and DHF appear to have an inhibiting effect also on the activity of LOX, whereas MOS, which did not significantly inhibit OTA production, had no effect on LOX activity. The presence of free hydroxyls in catecholic position in the molecule appears to be a determining factor for significantly inhibiting OTA biosynthesis. However, the presence of a methoxy group in C-7 in NEG could slightly lower the molecule's reactivity increasing OTA inhibition by this molecule at 5 µg/mL. Polyphenolic flavonoids present in edible plants may be easily synthesized and used to control OTA biosynthesis.


Assuntos
Aspergillus/efeitos dos fármacos , Aspergillus/metabolismo , Flavonoides/síntese química , Flavonoides/farmacologia , Ocratoxinas/biossíntese , Vias Biossintéticas/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Flavonas/química , Flavonas/farmacologia , Flavonoides/química , Lipoxigenase/metabolismo , Micotoxinas
9.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295812

RESUMO

Alzheimer's disease (AD), which is characterized by the presence of amyloid-ß (Aß) plaques and neurofibrillary tangles, accompanied by neurodegeneration, is the most common form of age-related neurodegenerative disease. Parkinson's disease (PD) is the second most common neurodegenerative disease after AD, and is characterized by early prominent loss of dopaminergic neurons in the substantia nigra pars compacta. As currently available treatments are not able to significantly alter the progression of these diseases, successful therapeutic and preventive interventions are strongly needed. In the course of our survey of substances from natural resources having anti-dementia and neuroprotective activity, we found nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin improved cognitive deficits and the pathological features of AD, such as Aß pathology, hyperphosphorylation of tau, and oxidative stress, in animal models of AD. In addition, nobiletin improved motor and cognitive deficits in PD animal models. These observations suggest that nobiletin has the potential to become a novel drug for the treatment and prevention of neurodegenerative diseases such as AD and PD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Citrus/química , Flavonas/farmacologia , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Biomarcadores , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Flavonas/química , Flavonas/uso terapêutico , Flavonoides/química , Flavonoides/uso terapêutico , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/prevenção & controle , Transdução de Sinais/efeitos dos fármacos
10.
Int J Mol Sci ; 20(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323961

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis, largely due to resistance to current radiotherapy and Temozolomide chemotherapy. The constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is evidenced as a pivotal driver of GBM pathogenesis and therapy resistance, and hence, is a promising GBM drug target. 5-acetyloxy-6,7,8,4'-tetramethoxyflavone (5-AcTMF) is an acetylated derivative of Tangeretin which is known to exert anticancer effects on breast, colon, lung, and multiple myeloma; however, its effect on GBM remains elusive. Herein, we reported that 5-AcTMF suppressed the viability and clonogenicity along with inducing apoptosis in multiple human GBM cell lines. Mechanistic analyses further revealed that 5-AcTMF lowered the levels of Tyrosine 705-phosphorylated STAT3 (p-STAT3), a canonical marker of STAT3 activation, but also dampened p-STAT3 upregulation elicited by Interleukin-6. Notably, ectopic expression of dominant-active STAT3 impeded 5-AcTMF-induced suppression of viability and clonogenicity plus apoptosis induction in GBM cells, confirming the prerequisite of STAT3 blockage for the inhibitory action of 5-AcTMF on GBM cell survival and growth. Additionally, 5-AcTMF impaired the activation of STAT3 upstream kinase JAK2 but also downregulated antiapoptotic BCL-2 and BCL-xL in a STAT3-dependent manner. Moreover, the overexpression of either BCL-2 or BCL-xL abrogated 5-AcTMF-mediated viability reduction and apoptosis induction in GBM cells. Collectively, we, for the first time, revealed the anticancer effect of 5-AcTMF on GBM cells, which was executed via thwarting the JAK2-STAT3-BCL-2/BCL-xL signaling axis. Our findings further implicate the therapeutic potential of 5-AcTMF for GBM treatment.


Assuntos
Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Flavonas/química , Flavonas/farmacologia , Glioblastoma/metabolismo , Fases de Leitura Aberta/genética , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Interleucina-6/metabolismo , Fator de Transcrição STAT3/genética , Proteína bcl-X/metabolismo
11.
Enzyme Microb Technol ; 129: 109361, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31307576

RESUMO

Amylosucrase (ASase) is a unique multifunctional enzyme exhibiting transglycosylation activity. In this study, the specificity of the transglycosylation activity of ASase was evaluated using several hydroxyflavones (HFVOs) and hydroxyflavanones (HFVAs). Our results reveal that the 3-OH and 7-OH positions of the mono-HFVOs and -HFVAs are resistant to transglycosylation by Deinococcus geothermalis ASase (DGAS), whereas the 6-OH and 4'-OH positions of the mono-HFVOs and -HFVAs exhibit relatively strong transglycosylation reactivities with the glucose donors released from sucrose by DGAS. Particularly, the 6-OH position is considerably more reactive (54-fold higher kcat) than the 4'-OH position in both HFVOs and HFVAs. Further, the transglycosylation reactions with di- and tri-HFVOs and HFVAs were also investigated and observed to exhibit similar results to those observed for the mono-HFVO and -HFVA molecules. The pH of the reaction influences the reactivity of certain hydroxyl residues, indicating that the pKa values of the hydroxyl groups may be crucial factors in the transglycosylation reactions. These observations help us understand the specificity of the transglycosylation activity of ASase and to predict the transglycosylation products of flavonoids.


Assuntos
Deinococcus/enzimologia , Flavanonas/metabolismo , Flavonas/metabolismo , Glucosiltransferases/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Deinococcus/química , Deinococcus/metabolismo , Flavanonas/química , Flavonas/química , Glucose/metabolismo , Glucosiltransferases/química , Glicosilação
12.
Eur J Med Chem ; 180: 253-267, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310917

RESUMO

Herein, we address repurposing hybrids of mosloflavone or 5,6,7-trimethoxyflavone with amide analogs of resveratrol from anticancer leads to novel potent anti-inflammatory chemical entities. To unveil the potent anti-inflammatory molecules, biological evaluations were initiated in LPS-induced RAW 264.7 macrophages at 1 µM concentration. Promising compounds were further evaluated at various concentrations. Multiple proinflammatory mediators were assessed including NO, PGE2, IL-6, TNF-α and IL-1ß. Compound 5z inhibited the induced production of NO, PGE2, IL-6, TNF-α and IL-1ß at the low 1 µM concentration by 44.76, 35.71, 53.48, 29.39 and 41.02%, respectively. Compound 5z elicited IC50 values as low as 2.11 and 0.98 µM against NO and PGE2 production respectively. Compounds 5q and 5g showed potent submicromolar IC50 values of 0.31 and 0.59 µM respectively against PGE2 production. Reverse docking of compound 5z suggested p38-α MAPK, which is a key signaling molecule within the pathways controlling the transcription of proinflammatory mediators, as the molecular target. Biochemical testing confirmed these compounds as p38-α MAPK inhibitors explaining its potent inhibition of proinflammatory mediators' production. Collectively, the results presented 5z as a promising compound for further development of anti-inflammatory agents for treatment of macrophages-and/or immune mediated inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Flavonas/farmacologia , Flavonoides/farmacologia , Mediadores da Inflamação/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Resveratrol/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Flavonas/química , Flavonoides/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Células RAW 264.7 , Resveratrol/química , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Pak J Pharm Sci ; 32(3): 1081-1089, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278723

RESUMO

A series of flavonoid derivatives, flavones (F1-F3) and flavonols (OF1-OF3) were synthesized. Their structures were confirmed through various spectroscopic techniques and elemental analysis. These were then tested for cytotoxic activity against mouse fibroblast (NIH 3T3), human endothelial cervical (HeLa) and breast (MCF7) cell lines in vitro by MTT assay. The flavonol series showed prominent potentials than the flavones. The compound OF2 in flavonols exhibited greater potentials MCF7 cell with IC50 value of 0.96µM and OF3 has 1.04µM. In contrast, the OF3 exhibited higher activity against HeLa cell with IC50 value of 0.51µM and OF2 has 1.06µM. The compounds OF2 and OF3 exhibited activity against mouse fibroblast (NIH 3T3) cell with IC50 values 2.48 and 1.24µM. The OF1 was found to be moderate to inactive against all cells. Cytotoxic screening of the tested flavones, F1 to F3 were also active against all cells but the activity was less in comparison to flavonol series of compounds suggestion the possible involvement of hydroxyl (OH) at position 3 in case of flavonols. These results indicated a cheering scaffold that may lead to innovation of potent anti-breast cancer activity.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Flavonas/síntese química , Flavonas/farmacologia , Flavonóis/síntese química , Flavonóis/farmacologia , Animais , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Flavonas/química , Flavonóis/química , Células HeLa , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Células NIH 3T3 , Relação Estrutura-Atividade
14.
J Agric Food Chem ; 67(29): 8168-8176, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31268318

RESUMO

Protein-based nanoparticles (NPs) with favorable properties including enhanced absorptivity and low toxicity still suffer a major challenge for rapid nutraceutical or drug release after oral administration. Hence, we introduced a secondary encapsulation for unstable factor to attain a controlled-release effect in a gastrointestinal environment. In this work, assembled nanoparticles engineered by nobiletin (NOB), zein, and tannin acid (TA) were first reported for drug delivery systems. The TA added was capable of obtaining further assembly to stabilize nobiletin in comparison with NOB-loaded zein NPs only. Sunflower pollens (SPGs) were selected as carriers for further oral delivery, while zein was chosen as a coating material for capping SPGs absolutely. As a result, the NOB/zein/TA NPs (NZT NPs) obtained had a stable size of 100 nm after 48 h. Besides, they could improve the chemical stability of NOB for at least 120 days at 4 °C compared with zein NPs (ZT NPs). Owing to the secondary capping by SPGs, the final system was able to release selectively via an oral route, that is, achieving no release in a gastric environment and slow release in an intestine environment. Generally, our research proposed a secondary protection model to prevent drug-loaded NPs from resolving after oral administration, which provided a new perspective for nutraceutical or drug encapsulation and controlled-release delivery.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Flavonas/química , Helianthus/química , Pólen/química , Administração Oral , Cápsulas/administração & dosagem , Cápsulas/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/instrumentação , Flavonas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Taninos/química , Zeína/química
15.
Molecules ; 24(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357486

RESUMO

Seventeen new flavone derivatives substituted at the 4'-OH position were designed, synthesized and evaluated for their anticancer and antibacterial activities. Among them, compounds 3, 4, 6f, 6e, 6b, 6c and 6k demonstrated the most potent antiproliferative activities against a human erythroleukemia cell line (HEL) and a prostate cancer cell line (PC3). The results also showed that the IC50 value of compounds 3, 4, 6f, 6e, 6b, 6c and 6k were close to that of the anticancer drug cisplatin (DDP) and lower than that of apigenin. All of the derivatives did not present antibacterial activities. The structure-activity relationships evaluation showed that the configuration of methyl amino acid might affect their biological activities.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Flavonas/química , Flavonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Flavonas/síntese química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
16.
ACS Chem Biol ; 14(7): 1536-1545, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31184855

RESUMO

Diversity-oriented synthesis (DOS) has historically focused on the development of small-molecule collections with considerable chemical diversity with the hypothesis that chemical diversity will lead to diverse biological activities. We took a systematic approach to DOS to develop a focused library of reduced flavones from γ-pyrones with diversity of appendage, stereochemistry, and chemical properties to determine which features of small molecules are most predictive of biological performance diversity. The effects of these systematic modifications on biodiversity were determined using Cell Painting and cytotoxicity assays to compare the results of multiple methods of assessment. We observed that a greater fraction of sp3 hybridized atoms (fsp3) does not always lead to enhanced biodiversity, that stereochemistry and appendage diversity both contribute to biodiversity, and that lipophilicity of the pyrone class of compounds correlates with biodiversity. These results will contribute to the development of a general algorithm to predict which chemical features should be considered during the synthesis of DOS libraries to create biological performance-diverse collections of small molecules for probe and drug discovery.


Assuntos
Antineoplásicos/química , Flavonas/química , Pironas/química , Bibliotecas de Moléculas Pequenas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Flavonas/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Oxirredução , Pironas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia
17.
Phytochemistry ; 164: 162-171, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31151063

RESUMO

In addition to the psychoactive constituents that are typically associated with Cannabis sativa L., there exist numerous other specialized metabolites in this plant that are believed to contribute to its medicinal versatility. This study focused on two such compounds, known as cannflavin A and cannflavin B. These prenylated flavonoids specifically accumulate in C. sativa and are known to exhibit potent anti-inflammatory activity in various animal cell models. However, almost nothing is known about their biosynthesis. Using a combination of phylogenomic and biochemical approaches, an aromatic prenyltransferase from C. sativa (CsPT3) was identified that catalyzes the regiospecific addition of either geranyl diphosphate (GPP) or dimethylallyl diphosphate (DMAPP) to the methylated flavone, chrysoeriol, to produce cannflavins A and B, respectively. Further evidence is presented for an O-methyltransferase (CsOMT21) encoded within the C. sativa genome that specifically converts the widespread plant flavone known as luteolin to chrysoeriol, both of which accumulate in C. sativa. These results therefore imply the following reaction sequence for cannflavins A and B biosynthesis: luteolin ► chrysoeriol ► cannflavin A and cannflavin B. Taken together, the identification of these two unique enzymes represent a branch point from the general flavonoid pathway in C. sativa and offer a tractable route towards metabolic engineering strategies that are designed to produce these two medicinally relevant Cannabis compounds.


Assuntos
Cannabis/química , Flavonas/biossíntese , Cannabis/metabolismo , Flavonas/química , Flavonas/metabolismo , Engenharia Metabólica , Estrutura Molecular
18.
Food Chem ; 293: 144-150, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151594

RESUMO

Nobiletin, a polymethoxyflavone mainly found in citrus fruits, have been reported to exhibit various beneficial biological activities for human health. It is an important bioactive compound in traditional Chinese medicine, Pericarpium Citri Reticulatae and Fructus Aurantii. To detect the contents of nobiletin in citrus and herb samples, we developed an indirect competitive enzyme-linked immunosorbent assay (icELISA) based on monoclonal antibodies. It possessed a median inhibition concentration (IC50) of 2.43 ±â€¯0.19 ng/mL and a working range of 0.52-12.3 ng/mL. The assay exhibited the average recoveries of 72.5-85.3% in citrus peel, pulp and juice samples. Moreover, eleven citrus cultivars samples and four herb samples were also detected by the icELISA. The nobiletin content varied in different citrus cultivars samples and herb samples, which were confirmed by the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS). These results indicated that the developed immunoassay was suitable for detecting nobiletin in citrus and herb samples.


Assuntos
Citrus/química , Flavonas/análise , Anticorpos Monoclonais/imunologia , Citrus/metabolismo , Ensaio de Imunoadsorção Enzimática , Flavonas/química , Flavonas/imunologia , Frutas/química , Frutas/metabolismo , Sucos de Frutas e Vegetais/análise , Haptenos/química , Haptenos/imunologia , Medicina Tradicional Chinesa
19.
Food Chem ; 293: 161-168, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151597

RESUMO

Olive leaves have become a promising source of phenolic compounds and flavonoids with high added value. Phenolic compounds and flavonoids are important sources of antioxidants and bioactives, and one of the processes used to effectively produce them is extraction via solvents, using aqueous ethanol solutions. To obtain the highest extraction yield per kg of biomass, olive leaves were extracted using a conventional technique (dynamic maceration) and an emerging technology, such as pressurized liquid extraction. Studies of the factors that influence these processes were performed: temperature, leaf moisture content, solvent/solid, and aqueous ethanol concentration were optimized using the central composite and Box-Behnken experiment designs. Pressurized liquid extraction resulted in more efficient oleuropein and luteolin-7-O-glucoside extraction than dynamic maceration. The operational conditions for maximizing the recovery of phenolic compounds and flavonoids and antioxidant capacity were determined to be 190 °C, leaf moisture content of 5%, and aqueous ethanol concentration of 80%.


Assuntos
Flavonas/química , Glucosídeos/química , Iridoides/química , Olea/química , Antioxidantes/química , Cromatografia Líquida de Alta Pressão , Flavonas/isolamento & purificação , Flavonoides , Glucosídeos/isolamento & purificação , Iridoides/isolamento & purificação , Olea/metabolismo , Fenóis/química , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Solventes/química , Temperatura Ambiente
20.
Artigo em Inglês | MEDLINE | ID: mdl-31233943

RESUMO

In the present study, a simple and efficient method based on orthogonal experimental design and macroporous resin chromatography was established for the first time for enrichment of polymethoxyflavones (PMFs) from the peels of Citrus reticulata 'Chachi' (CRC). The optimum conditions of extraction and enrichment process were as follows: use of a liquid to solid ratio of 1 to 14, two-hour extraction time repeated twice with 70% ethanol; use of HPD-450 macroporous resin, wash solvent of purified water and 25% aqueous ethanol, and 70% aqueous ethanol as desorption solvent. The purity of PMFs in the resulting extract reached 62.26%. Our data indicate that the PMFs purified could potently alleviate high-fat diet-induced hyperlipidaemia. The PMFs were nontoxic as determined by acute toxicity test. The method established was suitable for large-scale separation of PMFs from CRC peels and the PMFs might be developed as an anti-hyperlipidaemia agent or dietary supplement.


Assuntos
Cromatografia/métodos , Citrus/química , Flavonas/isolamento & purificação , Hipolipemiantes/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Animais , Feminino , Flavonas/administração & dosagem , Flavonas/química , Frutas/química , Humanos , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química
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