Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.554
Filtrar
1.
Zhongguo Zhong Yao Za Zhi ; 44(7): 1350-1356, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090291

RESUMO

Based on the fact that glycyrrhizic acid can form micelles in aqueous solution and play a role in solubilization, the optimal compatibility ratio between puerarin and glycyrrhizic acid was screened to prepare puerarin-glycyrrhizic acid dispersible tablets and investigate the dissolution of puerarin. The particle size, Zate potential and puerarin dissolution were compared among the micellar solutions with mass ratio of 7∶1, 6∶1, 5∶1, 4∶1, 3∶1 and 2∶1(puerarin to glycyrrhizic acid), and it was found that when the mass ratio of puerarin and glycyrrhizic acid was 5∶1, the micelle showed smallest particle size, uniform distribution, and largest puerarin dissolution, so mass ratio of 5∶1 was determined as the optimal condition. The formulation of puerarin-glycyrrhizic acid dispersible tablets was optimized by single factor and orthogonal test: puerarin 100.0 mg, glycyrrhizin 20.0 mg, polyvinylpolypyrrolidone 24.0 mg as disintegrating agent, microcrystalline cellulose 135.0 mg as stuffing bulking agent, hydroxypropyl methyl cellulose 18.0 mg as adhesive agent, magnesium stearate 2.7 mg as lubricant, and tablet weight of 300.0 mg. High-performance liquid chromatography(HPLC) method was used to determine the content of puerarin in dispersible tablets. Puerarin showed a good linear relationship(r=0.999 8) in the range of 15.5-248 g·L~(-1), with high precision(RSD<2.0%) and good repeatability(RSD<2.0%), and the recovery rate was 101.1%, RSD 0.89%. There was no significant difference in the quantity of puerarin in different batches of puerarin-glycyrrhizic acid dispersible tablets. When the artificial gastric juice was used as the dissolution medium, the dissolution of puerarin in puerarin-glycyrrhizic acid dispersible tablets could reach over 85% within 15 min. When phosphate buffer(pH 6.8) was used as the dissolution medium, the dissolution of puerarin in the puerarin-glycyrrhizic acid dispersible tablets had a faster dissolution rate in vitro, 99.8% in 30 min. Therefore, puerarin-glycyrrhizic acid dispersible tablets could improve the dissolution of puerarin in vitro due to the solubilization effect of glycyrrhizic acid.


Assuntos
Ácido Glicirrízico/química , Isoflavonas/química , Comprimidos , Solubilidade
2.
Fitoterapia ; 135: 85-89, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028818

RESUMO

A new phthalazinone derivative, named amycophthalazinone A (1), and a new isoflavonoid glycoside, 7-O-methyl-5-O-α-L-rhamnopyranosylgenestein (2), along with an isoflavonoid glycoside, 7-O-α-D-arabinofuranosyl daidzein (3) firstly found from natural sources, and eight known compounds (4-11), were isolated from the culture broth of the lichen-associated Amycolatopsis sp. YIM 130642. The structures of new compounds were elucidated on the basis of spectroscopic analysis. Compound 1 was the first example of naturally occurring phthalazinone derivative. The antimicrobial activities of all compounds towards five pathogenic strains were evaluated by a broth microdilution assay. Compound 1 exhibited the most potent inhibitory activity against Staphylococcus aureus, Salmonella typhi, and Candida albicans with MIC values of 32, 32, and 64 µg/mL, respectively.


Assuntos
Actinobacteria/fisiologia , Anti-Infecciosos/farmacologia , Glicosídeos/farmacologia , Isoflavonas/farmacologia , Líquens/química , Ftalazinas/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Candida albicans/efeitos dos fármacos , Glicosídeos/química , Glicosídeos/isolamento & purificação , Isoflavonas/química , Isoflavonas/isolamento & purificação , Líquens/microbiologia , Estrutura Molecular , Ftalazinas/química , Ftalazinas/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos
3.
Mol Brain ; 12(1): 36, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961625

RESUMO

Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover (Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABAA receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/terapia , Inflamação/patologia , Isoflavonas/uso terapêutico , Animais , Ansiolíticos/farmacologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Comportamento Animal/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Adjuvante de Freund , Isoflavonas/química , Isoflavonas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Modelos Moleculares , NF-kappa B/metabolismo , NF-kappa B/farmacocinética , Dor/tratamento farmacológico , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
4.
J Agric Food Chem ; 67(17): 4817-4823, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30973720

RESUMO

Ficus carica is an Asian species of flowering plant belonging to the genus Ficus of the family Moraceae, native to Western Asia and the Middle East. Its fruits, usually known as common fig or fig, have been consumed as a very popular health-promoting fruit worldwide since ancient times. To investigate the potential health-promoting chemical constituents of the fruits of F. carica, a systematic phytochemical study on its fruits was therefore carried out. In our study, four new structurally diverse prenylated isoflavone derivatives, ficucaricones A-D (1-4), along with 12 known analogues (5-16) were separated from the fruits of F. carica. Their chemical structures were ambiguously elucidated based on extensive spectroscopic methods. The anti-inflammatory effects and antiproliferative activities of these isolated prenylated isoflavone derivatives were tested. Prenylated isoflavone derivatives (1-16) displayed remarkable inhibitory effects against nitric oxide (NO) production with the IC50 values ranging from 0.89 ± 0.05 to 8.49 ± 0.18 µM, comparable to that of the positive control (hydrocortisone). Furthermore, compounds 1-16 also exhibited pronounced antiproliferative activities against diverse human cancer cell lines in vitro, holding the IC50 values ranging from 0.18 ± 0.03 to 18.76 ± 0.09 µM. These findings indicate that regular consumption of the fruits of F. carica may help to prevent the occurrence of inflammatory diseases and tumors. Moreover, the isolation and characterization of these prenylated isoflavone derivatives possessing remarkable anti-inflammatory effects and antiproliferative activities could be meaningful to the discovery of new anti-inflammatory and antitumor agents.


Assuntos
Anti-Inflamatórios/química , Ficus/química , Inibidores do Crescimento/química , Isoflavonas/química , Extratos Vegetais/química , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Frutas/química , Inibidores do Crescimento/farmacologia , Humanos , Isoflavonas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Extratos Vegetais/farmacologia , Prenilação , Células RAW 264.7
5.
Molecules ; 24(5)2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30841642

RESUMO

: Kudzu (Pueraria thunbergiana Benth.) has long been used as a food and medicine for many centuries. The root is the most commonly used portion of the plant, but the aerial parts are occasionally used as well. In this study, we investigated the constituent compounds and biological activities of the aerial parts, leaves, stems, and sprouts, and compared their constituents and activities with those of roots. Leaf extract showed a significantly higher TPC level at 59 ± 1.6 mg/g and lower free radical scavenging (FRS) values under 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS), and NO inhibition at 437 ± 11, 121 ± 6.6 µg/mL and 107 ± 4.9 µg/mL, respectively, than those of sprout, stem, and root extract. Leaf extract also significantly suppressed lipopolysaccharide (LPS)-mediated gene expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). The main components of leaf extract were found to be genistin and daidzin. This study suggests that the leaves of kudzu are a good source of biological activities and isoflavones that can be used in functional or medicinal foods and cosmetics for the prevention or treatment of diseases related to inflammation and oxidative stress.


Assuntos
Isoflavonas/química , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Raízes de Plantas/química , Pueraria/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/química , Estresse Oxidativo , Fenóis/química , Células RAW 264.7
6.
J Pharm Biomed Anal ; 169: 60-69, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30836247

RESUMO

Naoluoxintong decoction (NLXTD) is a traditional Chinese formula which has been used for the management of ischemic stroke in China for two hundred years. In this study, we developed a comprehensive and reliable analytical method to qualitatively analyze the components in NLXTD. This novel method was based on three-dimensional ultra-fast high performance liquid chromatography coupled with diode array detector (3D-UPLC-DAD) with an additional component validation method via incorporation of the mixture standard compounds during the verification step. In addition, the relationship between active components and "Monarch drug, Minster drug, Assistant drug, Guide drug" were determined. Our results showed that gradient elution with the mobile phase of 0.02% formic acid and methanol was the optimum condition to separate peaks. A total of 35 common peaks were established by comparing ten batches of NLXTD, and eight components were identified, including Calycosin, Calycosin-7-O-ß-d-glucoside and Ononin in Astragali radix (Monarch drug); Ligustrazine in Chuanxiong Rhizoma (Minster drug); 4-Hydroxbenzyl alcohol and Parishin A in Gastrodiae rhizome (Assistant drug); Ferulic acid in Angelicae sinensis radix (Guide drug). The validation method of verification by adding mixture standard compounds combined with 3D-UPLC-DAD method, with the merits of greater resolution, higher speed of analysis and higher sensitivity, provided a semi-quantitative and qualitative analysis method to assess traditional Chinese medicinal prescription consisting of many bio-active components. Finally, our study has provided systemic and scientific evidence to explain the relationship between the bio-active components in the NLXTD and traditional Chinese medicine theory.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Rizoma/química , China , Ácidos Cumáricos/química , Glucosídeos/química , Isoflavonas/química , Medicina Tradicional Chinesa/métodos , Extratos Vegetais/química , Sensibilidade e Especificidade
7.
J Pharm Biomed Anal ; 169: 127-132, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30861404

RESUMO

The isolated perfused rat lung (IPL), coupled with high performance liquid chromatography\tandem mass spectrometry analysis (HPLC-ESI-MSn), has been developed as a tool for screening bioactive components in Glycyrrhiza uralensis Fisch. (GU). First, IPL was perfused with the water extract of GU (EGU), the bioactive components in the EGU would selectively combine to the receptors or channels of lung. By changing the pH of perfused solution, the combined components were eluated and then detected by HPLC-ESI-MSn. Four compounds were detected in the desorption eluate of IPL, among these compounds, liquiritin (1), ononin (2) and glycyrrhizic acid (4) were identified by comparing with the chromatography of the standards, while licorice-saponin G2 (3) were determined by analysis of the structure clearage characterization of mass spectrometry. Then, due to the lack of compound 3 sample, compounds 1, 2 and 4 with respective concentrations of 50 µM, 5 µM, 500 nM, 50 nM and 5 nM were applied to evaluate the protective effect of pulmonary epithelial cells (PEC, A549 cell) injury induced by lipopolysaccharide (LPS) for anti-inflammatory activity assessment. The results showed that except the 5 nM group of compound 1, 5 nM and 50 nM groups of compound 2, all other groups could remarkably inhibit the PEC injury (vs LPS group, 2-500 nM groups: p < 0.05; other groups: p < 0.01), all compound showed the dose-dependent effect. In conclusion, IPL coupled with HPLC-ESI-MSn was successfully used to screen the anti-inflammatory components of GU for the first time. The application of IPL coupled with HPLC-ESI-MSn for screening bioactive components of TCMs is rapid, convenient and reliable, and the isolated perfused technology could be extended to isolated heart, liver, kidney, and so on.


Assuntos
Glycyrrhiza uralensis/química , Pulmão/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células A549 , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/métodos , Flavanonas/química , Flavanonas/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Glycyrrhiza/química , Ácido Glicirrízico/química , Ácido Glicirrízico/farmacologia , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Ratos , Ratos Wistar , Saponinas/química , Saponinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem/métodos
8.
Phytomedicine ; 58: 152853, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30836216

RESUMO

BACKGROUND: While incidences of cancer are continuously increasing, drug resistance of malignant cells is observed towards almost all pharmaceuticals. Several isoflavonoids and flavonoids are known for their cytotoxicity towards various cancer cells. PURPOSE: The aim of this study was to determine the cytotoxicity of isoflavones: osajin (1), 5,7-dihydroxy-4'-methoxy-6,8-diprenylisoflavone (2) and biflavonoids: chamaejasmin (3), 7,7″-di-O-methylchamaejasmin (4) and campylospermone A (5), a dimeric chromene [diphysin(6)] and an ester of ferullic acid with long alkyl chain [erythrinasinate (7)] isolated from the stem bark and roots of the Kenyan medicinal plant, Ormocarpum kirkii. The mode of action of compounds 2 and 4 was further investigated. METHODS: The cytotoxicity of compounds was determined based on the resazurin reduction assay. Caspases activation was evaluated using the caspase-Glo assay. Flow cytometry was used to analyze the cell cycle (propodium iodide (PI) staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). CCRF-CEM leukemia cells were used as model cells for mechanistic studies. RESULTS: Compounds 1, 2 and 4 displayed IC50 values below 20 µM towards CCRF-CEM and CEM/ADR5000 leukemia cells, and were further tested towards a panel of 7 carcinoma cells. The IC50 values of the compounds against carcinoma cells varied from 16.90 µM (in resistant U87MG.ΔEGFR glioblastoma cells) to 48.67 µM (against HepG2 hepatocarcinoma cells) for 1, from 7.85 µM (in U87MG.ΔEGFR cells) to 14.44 µM (in resistant MDA-MB231/BCRP breast adenocarcinoma cells) for 2, from 4.96 µM (towards U87MG.ΔEGFRcells) to 7.76 µM (against MDA-MB231/BCRP cells) for 4, and from 0.07 µM (against MDA-MB231 cells) to 2.15 µM (against HepG2 cells) for doxorubicin. Compounds 2 and 4 induced apoptosis in CCRF-CEM cells mediated by MMP alteration and increased ROS production. CONCLUSION: The present report indicates that isoflavones and biflavonoids from Ormocarpum kirkii are cytotoxic compounds with the potential of being exploited in cancer chemotherapy. Compounds 2 and 4 deserve further studies to develop new anticancer drugs to fight sensitive and resistant cancer cell lines.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Biflavonoides/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Fabaceae/química , Isoflavonas/farmacologia , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Biflavonoides/química , Caspases/efeitos dos fármacos , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Isoflavonas/química , Quênia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Casca de Planta/química , Extratos Vegetais/química , Raízes de Plantas/química , Plantas Medicinais , Espécies Reativas de Oxigênio/metabolismo
9.
Int J Pharm ; 561: 228-235, 2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-30836152

RESUMO

Glabridin, a compound in the root extract of Glycyrrhiza glabra, has been identified as an effective tyrosinase inhibitor. Applied on skin, melanin synthesis is inhibited, making glabridin an interesting candidate for skin whitening or for the treatment of age spots. However, main obstaclefor its practical use is its low dermal bioavailability, caused by its poor water solubility. In this work smartPearls technology was used to increase the glabridins water solubility. smartPearls consist of silica particles with mesopores in which actives can be loaded. By this, actives are stabilized in amorphous state and simultaneously finely distributed in nm-range. Both amorphization and nanoization are well known approaches to increase saturation solubilities. In smartPearls these approaches are combined. In the first step, glabridin smartPearls formulation was developed, screening systematically the suitability of 4 different silicas varying in their pore sizes (3, 6, 10, 17 nm). Also, most suited filling level of glabridin was determined (25, 50, 80% referred to total pore volume of respective silica). Silica loading was performed by the immersion-evaporation method, resulting in pores filled with glabridin from bottom to top. By light microscopy, dynamic scanning calorimetry and X-ray diffraction the sample with 6 nm pore size and filling levels of 25% and 50% have been verified to be completely amorphous. Highest physical storage stability of 7 months up to now was obtained for the 25% filled sample. In the next step, concept of increased saturation solubility for smartPearls was proven. Dissolution profiles were recorded in situ for glabridin smartPearls and compared to glabridin raw drug powder. Both saturation solubility and dissolution velocity were remarkably improved. The water solubility for example increased by a factor of more than 4. This makes glabridin smartPearls promising for creating skin products with improved dermal bioavailability.


Assuntos
Isoflavonas/química , Nanopartículas/química , Fenóis/química , Dióxido de Silício/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Solubilidade
10.
Biomater Sci ; 7(5): 2152-2164, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30896685

RESUMO

Nano-drug delivery systems are widely used in medical diagnoses, tumour drug delivery and other fields due to their unique advantages. Thus, the preparation of more biocompatible nanocarriers by modifying natural materials has become a research hotspot in recent years. As a type of abundant and environment-friendly natural material, puerarin has been proven to be effective in the treatment of many diseases. However, its low solubility and low oral utilization limit its use. In this study, a novel biocompatible nanomaterial was developed. Puerarin was modified with an unsaturated olefin via acryloyl chloride and the amphiphilic polymer poly-puerarin was finally obtained through free radical polymerization, which was used in the preparation of a drug delivery system. Poly-puerarin nanoparticles (PPue NPs) were prepared by nanoprecipitation and used as a platform to load paclitaxel (PPue@PTX NPs). Physicochemical characterization showed that the nanoparticle size was around 70 nm and the drug loading efficiency of PTX was up to 23.8%. The cytotoxicity test revealed that the modified puerarin derivatives, PPue, exhibited good biocompatibility even at large doses of 100 µg mL-1 and the PPue@PTX NPs still maintained the excellent anti-cancer effect of PTX. The in vitro cellular uptake assay demonstrated that the PPue@PTX NPs were rapidly uptaken by CT26 cells. In the in vivo experiments, the PPue@PTX NPs featured rapid aggregation and slow clearance and the most significant effect of inhibiting tumour growth among all the treatment groups. Therefore, our work provides a new strategy for the modification of natural drugs and PPue is expected to become a new safe and reliable nano-drug delivery platform.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Isoflavonas/química , Isoflavonas/síntese química , Segurança , Animais , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Nanopartículas/química , Paclitaxel/química
11.
Molecules ; 24(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909396

RESUMO

Background: The damage to intestinal barrier function plays an important role in the development of obesity and associated diseases. Soy isoflavones are effective natural active components for controlling obesity and reducing the level of blood lipid. Here, we explored whether these effects of soy isoflavones were associated with the intestinal barrier function. Methods and Results: The obese rat models were established by high fat diet feeding. Then, those obese rats were supplemented with soy isoflavones at different doses for 4 weeks. Our results showed that obesity induced the expressions of pro-inflammatory cytokines, decreased the anti-inflammatory cytokine (IL-10) expression, elevated intestinal permeability, altered gut microbiota and exacerbated oxidative damages in colon. The administration of soy isoflavones reversed these changes in obese rats, presenting as the improvement of intestinal immune function and permeability, attenuation of oxidative damage, increase in the fraction of beneficial bacteria producing short-chain fatty acids and short-chain fatty acid production, and reduction in harmful bacteria. Furthermore, soy isoflavones blocked the expressions of TLR4 and NF-κB in the colons of the obese rats. Conclusions: Soy isoflavones could improve obesity through the attenuation of intestinal oxidative stress, recovery of immune and mucosal barrier, as well as re-balance of intestinal gut microbiota.


Assuntos
Colo/efeitos dos fármacos , Colo/imunologia , Dieta Hiperlipídica/efeitos adversos , Imunomodulação/efeitos dos fármacos , Isoflavonas/farmacologia , Obesidade/etiologia , Animais , Biodiversidade , Biomarcadores , Peso Corporal/efeitos dos fármacos , Colo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Expressão Gênica , Regulação da Expressão Gênica , Imunomodulação/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Isoflavonas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais , Ratos , Transdução de Sinais , Soja/química , Receptor 4 Toll-Like/metabolismo
12.
Eur J Med Chem ; 168: 207-220, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30822710

RESUMO

A series of novel isoflavone analogs were designed, synthesized, and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease. In vitro evaluations revealed that some ligands had multifunctional profiles, including potent blockage of histamine 3 receptor (H3R), excellent inhibition of acetylcholinesterase (AChE), neuroprotective effects and anti-neuroinflammatory properties. Among these derivatives, compound 9b exhibited the highest ability to block H3R (IC50 = 0.27 µM) and good inhibitory activity against AChE (IC50 = 0.08 µM). Additionally, compound 9b showed obvious neuroprotective effect on SH-SY5Y by preventing copper-induced neuronal damage and potent anti-neuroinflammatory activity by inhibiting the production of inflammatory factors on BV-2 cells. A molecular modeling study revealed that 9b acts as a mixed-type inhibitor that interacts simultaneously with H3R and AChE. Moreover, in vivo data revealed that compound 9b did not cause acute toxicity in mice at doses up to 1000 mg/kg, and had desirable pharmacokinetic properties, as well as a good blood-brain barrier (BBB) permeability (log BB = 1.24 ±â€¯0.07). Further studies demonstrated that chronic oral treatment with 9b significantly improved cognitive dysfunction in scopolamine-induced AD mice in the step-down passive avoidance test. Taken together, the present study showed that compound 9b is a promising multifunctional drug candidate for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Isoflavonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Isoflavonas/síntese química , Isoflavonas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade
13.
Molecules ; 24(6)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893792

RESUMO

Phytoestrogens are naturally occurring nonsteroidal phenolic plant compounds that, due to their molecular structure and size, resemble vertebrate steroids estrogens. This review is focused on plant flavonoids isoflavones, which are ranked among the most estrogenic compounds. The main dietary sources of isoflavones for humans are soybean and soybean products, which contain mainly daidzein and genistein. When they are consumed, they exert estrogenic and/or antiestrogenic effects. Isoflavones are considered chemoprotective and can be used as an alternative therapy for a wide range of hormonal disorders, including several cancer types, namely breast cancer and prostate cancer, cardiovascular diseases, osteoporosis, or menopausal symptoms. On the other hand, isoflavones may also be considered endocrine disruptors with possible negative influences on the state of health in a certain part of the population or on the environment. This review deals with isoflavone classification, structure, and occurrence, with their metabolism, biological, and health effects in humans and animals, and with their utilization and potential risks.


Assuntos
Isoflavonas/metabolismo , Animais , Equol/química , Equol/classificação , Equol/metabolismo , Genisteína/química , Genisteína/classificação , Genisteína/metabolismo , Humanos , Isoflavonas/química , Isoflavonas/classificação , Fitoestrógenos/química , Fitoestrógenos/classificação , Fitoestrógenos/metabolismo
14.
Nutrients ; 11(2)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769910

RESUMO

In this study, we investigated whether (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone, a homoisoflavonoid compound isolated from Portulaca oleracea L., protects INS-1 pancreatic ß cells against glucotoxicity-induced apoptosis. Treatment with high glucose (30 mM) induced apoptosis in INS-1 pancreatic ß cells; however, the level of cell viability was significantly increased by treatment with (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone. Treatment with 10⁻20 µM of (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone dose-dependently increased cell viability and significantly decreased the intracellular level of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide levels in INS-1 pancreatic ß cells pretreated with high glucose. These effects were associated with increased anti-apoptotic Bcl-2 protein expression, while reducing pro-apoptotic Bax, cytochrome C, and caspase 9 protein expression. Treatment with (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone reduced the apoptosis previously induced by high-level glucose-treatment, according to annexin V/propidium iodide staining. These results demonstrate that (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone may be useful as a potential therapeutic agent to protect INS-1 pancreatic ß cells against high glucose-induced apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Glucose/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Isoflavonas/farmacologia , Portulaca/química , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/administração & dosagem , Humanos , Isoflavonas/química , Estrutura Molecular , Componentes Aéreos da Planta/química , Substâncias Protetoras
15.
Food Chem ; 275: 273-281, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30724197

RESUMO

One challenge for daidzein delivery is how to efficiently suppress its precipitation/crystallization in a lipid-based system. In this work, whey protein isolate (WPI) with different thermal treatment was employed as a hydrophobic drug crystallization depressor and its interaction mechanism with daidzein was studied. The results indicated WPI aggregated to form nanoparticles (below 300 nm) in the presence of daidzein. Thermal denaturing (85 °C, 20 min) improved the binding affinity for daidzein with Ka = 1.165 × 104 M-1, about 1.5-fold higher than that of the native protein (Ka = 7.285 × 103 M-1). Hydrophobic interaction was the major driving forces based on thermodynamic calculation. The as-obtained protein-based nanocomplexes efficiently inhibited daidzein crystallization, enhancing its solubility at least 2-fold with promoted stability (stable at 4 °C for at least 2 months). These findings provide new ideas for the application of WPI, showing great potential to be directly used in lipid nanocarrier system as crystallization depressor.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Isoflavonas/química , Nanopartículas/química , Proteínas do Soro do Leite/química , Cristalização , Temperatura Alta , Interações Hidrofóbicas e Hidrofílicas , Isoflavonas/metabolismo , Tamanho da Partícula , Desnaturação Proteica , Solubilidade , Espectrometria de Fluorescência , Termodinâmica , Proteínas do Soro do Leite/metabolismo
16.
Cell Biol Int ; 43(3): 323-332, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30632644

RESUMO

Calycosin has been reported to have a strong osteogenic activity and a positive correlation with anti-osteoporosis effects. However, its precise mechanism of action remains unclear. Since insulin-like growth factor 1 receptor (IGF1R) signaling and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signaling have been shown to play a pivotal role in regulating osteogenesis, we hypothesized that the osteogenic activity of calycosin is mediated by these signaling pathways. Rat calvarial osteoblasts (ROBs) were cultured in osteogenic medium containing calycosin with or without GSK1904529A (GSK) or LY294002 (LY) (inhibitors of IGF1R and PI3K, respectively). The effects on cell proliferation, alkaline phosphatase (ALP) activity, calcified nodules, mRNA or protein expression of osteogenic genes [alkaline phosphatase (Alpl), collagen type I (Col1a1), runt-related transcription factor 2 (Runx2), Osterix, and bone morphogenetic protein 2 (Bmp2)], and phosphorylation of IGF1R and Akt were examined. The present results showed that calycosin enhanced cell proliferation, ALP activity and Alizarin Red-S staining in a dose-dependent manner in the range of 10-8 -10-6 M, while an inhibitory effect was observed at 10-5 M. Treatment at the optimal concentration (10-6 M, a physiologically achievable concentration) increased mRNA levels of osteogenic genes and phosphorylation of IGF1R and Akt. Furthermore, treatment with GSK or LY partly reversed the effects of calycosin on ROBs, as indicated by the decreases in calycosin-induced ALP activity, calcified nodules and osteogenic gene expression. These results suggest that the osteogenic effect of calycosin partly involves the IGF1R/PI3K/Akt signaling pathway.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Isoflavonas/farmacologia , Osteoblastos/citologia , Osteogênese/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo , Crânio/citologia , Fosfatase Alcalina/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Isoflavonas/química , Morfolinas/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
17.
Enzyme Microb Technol ; 122: 19-25, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30638505

RESUMO

Fructosylation can significantly improve the solubility, stability and bioactivity of phenolic compounds, increasing their health benefits. Levansucrase from Gluconacetobacter diazotrophicus (LsdA, EC 2.4.1.10) was found to transfer the fructosyl unit of sucrose to different classes of phenolic compounds. Among the various acceptors tested, the isoflavone puerarin and the phenol coniferyl alcohol were the most efficiently fructosylated compounds, with conversion rates of 93% and 25.1%, respectively. In both cases, mono-, di-, and trifructosides were synthesized at a ratio of 37:14:1 and 32:8:1, respectively. Structural characterization of the puerarin mono-fructoside revealed that the enzyme transferred the fructosyl moiety of sucrose to the O6-position of the glucosyl unit of puerarin. The water solubility of fructosyl-ß-(2→6)-puerarin was increased 23-fold, up to 16.2 g L-1, while its antioxidant capacity was only decreased 1.25-fold compared with that of puerarin.


Assuntos
Proteínas de Bactérias/metabolismo , Gluconacetobacter/enzimologia , Hexosiltransferases/metabolismo , Fenóis/metabolismo , Sacarose/metabolismo , Biocatálise , Glicosilação , Isoflavonas/química , Isoflavonas/metabolismo , Fenóis/química , Solubilidade
18.
Int J Mol Sci ; 20(2)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669260

RESUMO

Understanding the role of substituents is of great importance for the preparation of novel phenolic compounds with enhanced antioxidative properties. In this work, the antioxidative activity of isoflavonoid derivatives with different substituents placed at the C2 position was determined by density functional theory (DFT) calculations. The bond dissociation enthalpy (BDE), ionization potential (IP), and proton affinity (PA) related to hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) mechanisms were calculated. The strongest antioxidative group of isoflavonoid is not altered by the substituents. Excellent correlations were found between the BDE/IP/PA and Hammett sigma constants. Equations obtained from linear regression can be useful in the selection of suitable candidates for the synthesis of novel isoflavonoids derivatives with enhanced antioxidative properties. In the gas and benzene phases, the electron-donating substituents would enhance the antioxidative activity of isoflavonoids via weakening the BDE of 4'-OH. In water phase, they will reduce the antioxidative by strengthening the PA of 7-OH. Contrary results occur for the electron-withdrawing groups. In addition, the electronic effects of substituents on the BDE/IP/PA have also been analyzed.


Assuntos
Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Isoflavonas/química , Isoflavonas/farmacologia , Ligações de Hidrogênio , Estrutura Molecular , Prótons , Relação Estrutura-Atividade
19.
Int J Pharm ; 557: 170-177, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30597264

RESUMO

Because numerous challenges limit the effective oral delivery of protein and peptide drugs, we developed promising chitosan (CS)-modified, dual drug-loaded nanoparticles (NPs) simultaneously containing salmon calcitonin (sCT) and puerarin (PR) (CS-sCT/PR-NPs), and to explore the potential of PR as a protease inhibitor. This oral delivery system showed efficient encapsulation of sCT (75.7%) and PR (50.9%), protection of encapsulated sCT and PR from premature release in simulated gastric fluid (SGJ, pH 1.2), and sustained-release behavior in phosphate buffer saline (PBS, pH 7.4). CS-sCT/PR-NPs were capable of sequential drug-release in which PR was partially released prior to sCT, allowing PR to play a role of enzyme inhibitor before sCT release. Compared with CS-sCT-NPs, CS-sCT/PR-NPs were more stable in simulated intestinal fluid containing pancreatinum. The internalization of fluorescein isothiocyanate-labeled sCT (FITC-sCT) by Caco-2 cells increased when incorporated into NPs compared with free sCT. In vivo, the oral absolute bioavailability of sCT in CS-sCT/PR-NPs was 12.52 ±â€¯1.83%, approximately 1.74-fold higher than that of the NPs not co-loaded with PR. In conclusion, the CS-based NPs and introduction of PR as a protease inhibitor improved the oral bioavailability of sCT and had potential to be developed as an oral delivery system of peptide drug.


Assuntos
Calcitonina/administração & dosagem , Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Isoflavonas/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Calcitonina/química , Calcitonina/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Quitosana/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Absorção Intestinal , Secreções Intestinais/química , Isoflavonas/química , Isoflavonas/farmacocinética , Nanopartículas/química , Ratos Sprague-Dawley
20.
J Biochem Mol Toxicol ; 33(5): e22296, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30672062

RESUMO

Puerarin belongs to one of the most familiar tradition medicines of China, but adverse effects of puerarin during the clinical treatment have been found for years, the mechanisms of which remain unclear. In this study, toxic mechanisms of puerarin on the structure and function of catalase were studied by multiple spectroscopic techniques, isothermal titration calorimetric measurement, and molecular docking methods in vitro. Results showed puerarin could inhibit the activity of catalase due to direct interactions between puerarin and catalase, resulting in conformational and functional changes of the enzyme. To be specific, puerarin statically quenched catalase fluorescence, bound into the active site channel of catalase, hindered the path of the catalytic substrate (H2 O2 ), affected its skeleton conformation and secondary structure, and interacted with the enzymatically related residues through hydrophobic interactions (ΔH > 0 and ΔS > 0) spontaneously (ΔG < 0). This study illustrates potential adverse effects of puerarin, which should catch more attentions during the clinical diagnosis.


Assuntos
Catalase/química , Isoflavonas/química , Simulação de Acoplamento Molecular , Animais , Catálise , Bovinos , Peróxido de Hidrogênio/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA