RESUMEN

OBJECTIVE: To investigate the protective effect of 5-hydroxy-6,7-dimethoxyflavone (5-HDF), a compound extracted from Elsholtzia blanda Benth., against lung injury induced by H1N1 influenza virus and explore its possible mechanism of action. METHODS: 5-HDF was extracted from Elsholtzia blanda Benth. using ethanol reflux extraction and silica gel chromatography and characterized using NMR and MS analyses. In an A549 cell model of H1N1 influenza virus infection (MOI=0.1), the cytotoxicity of 5-HDF was assessed using MTT assay, and its effect on TRAIL and IL-8 expressions was examined using flow cytometry; Western blotting was used to detect the expression levels of inflammatory, apoptosis, and ferroptosis-related proteins. In a mouse model of H1N1 influenza virus infection established by nasal instillation of 50 µL H1N1 virus at the median lethal dose, the effects of 30 and 60 mg/kg 5-HDF by gavage on body weight, lung index, gross lung anatomy and lung histopathology were observed. RESULTS: 5-HDF exhibited no significant cytotoxicity in A549 cells within the concentration range of 0-200 µg/mL. In H1N1-infected A549 cells, treatment with 5-HDF effectively inhibited the activation of phospho-p38 MAPK and phospho-NF-κB p65, lowered the expressions of IL-8, enhanced the expression of anti-ferroptosis proteins (SLC7A11 and GPX4), and inhibited the expressions of apoptosis markers PARP and caspase-3 and the apoptotic factor TRAIL. In H1N1-infected mice, treatment with 5-HDF for 7 days significantly suppressed body weight loss and increment of lung index and obviously alleviated lung tissue pathologies. CONCLUSION: 5-HDF offers protection against H1N1 influenza virus infection in mice possibly by suppressing H1N1-induced ferroptosis, inflammatory responses, and apoptosis via upregulating SLC7A11 and GPX4, inhibiting the activation of phospho-NF-κB p65 and phospho-p38 MAPK, and decreasing the expression of cleaved caspase3 and cleaved PARP.

Asunto(s)

Ferroptosis , Flavonas , Inflamación , Subtipo H1N1 del Virus de la Influenza A , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Humanos , Células A549 , Ratones , Animales , Ferroptosis/efectos de los fármacos , Flavonas/farmacología , Apoptosis/efectos de los fármacos , Interleucina-8/metabolismo , Pulmón/patología , Lamiaceae/química , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Factor de Transcripción ReIA/metabolismo , Caspasa 3/metabolismo

RESUMEN

(-)-Epigallocatechin-3-O-gallate (EGCG) is one of the major components of green tea polyphenol. Previous studies have shown that EGCG induces cancer-specific cell death in vitro and in vivo without causing severe side effects. However, the anti-cancer effect of EGCG alone is limited. 5,7-dimethoxyflavone (5,7-DMF), one of the principal functional components of black ginger (Kaempferia parviflora), also exerts anti-cancer effects. Here, we show that 5,7-DMF synergistically enhances the anti-cancer effect of EGCG in multiple myeloma cells by potentiating EGCG-induced intracellular cyclic guanosine monophosphate (cGMP) production. Moreover, the combination of EGCG and 5,7-DMF induces apoptotic cell death in multiple myeloma cells, and this is accompanied by activation of the cGMP/acid sphingomyelinase (ASM)/cleaved caspase-3 pathway. In conclusion, we have shown that 5,7-DMF enhances the anti-cancer effect of EGCG by upregulating cGMP in multiple myeloma cells.

Asunto(s)

Catequina , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Línea Celular Tumoral , Apoptosis , Catequina/farmacología

RESUMEN

This study was undertaken to analyse the potential bioactivities including antibacterial, antioxidant and antidiabetic derived from the methanolic extract and the column chromatography ethyl acetate fraction (AcOEt Fr) of Horsfieldia spicata leaves. Methanolic extract and 4 other fractions was calculated for total phenol and flavonoid contents along with tested for antibacterial, antioxidant and antidiabetic properties. Interestingly, the AcOEt Fr had the highest value for total flavonoid content and the best antioxidant, and antidiabetic activities. Therefore, the AcOEt Fr was further separated using column chromatography technique for obtaining 9 selected fractions namely fraction 1 (F1) - fraction 9 (F9) which were further tested. The results showed that the AcOEt column chromatography fractions namely F2, F3, F4 and F6 had the best clear inhibition antibacterial value against all bacterial tested. In addition, these fractions also exhibited better Minimum Inhibitory Concentrations (MIC) and Minimum Bactericidal Concentrations (MBC) values than others. Antioxidant, 2,2-diphenylpicrylhydrazyl (DPPH) assayed indicated that AcOEt Fr had the strongest IC50 value of 47.30 µg/mL. Further, F4 column chromatography fraction showed the best inhibition against α-Glucosidase enzyme related to antidiabetic activity with an IC50 value of 6.11 µg/mL. Liquid chromatography tandem-mass spectrometry (LC/MS/MS) analysis identified that F4 derived from AcOEt fraction had several compounds belonging to the flavonoid and phenolics such as 3',5-dihydroxy-7,4'-dimethoxyflavone, 5,7-dihydroxy-3-(4'-hydroxybenzyl)chromone, and Kadsurenin I.

Asunto(s)

Antioxidantes , Hipoglucemiantes , Antioxidantes/química , Hipoglucemiantes/farmacología , Espectrometría de Masas en Tándem , Extractos Vegetales/química , Flavonoides/química , Antibacterianos/farmacología , Antibacterianos/análisis , Metanol , Fenoles/farmacología , Fenoles/análisis , Hojas de la Planta/química

RESUMEN

The important pathway toward liver fibrosis is the TGF-ß1-induced activation of hepatic stellate cells (HSCs). To discover chemicals to inhibit liver fibrosis, we screened 3000 chemicals using cell array system where human HSCs line LX2 cells are activated with TGF-ß1. We discovered 3,7-dimethoxyflavone (3,7-DMF) as a chemical to inhibit TGF-ß1-induced activation of HSCs. In the thioacetamide (TAA)-induced mouse liver fibrosis model, 3,7-DMF treatment via intraperitoneal or oral administration prevented liver fibrosis as well as reversed the established fibrosis in the separate experiments. It also reduced liver enzyme elevation, suggesting protective effect on hepatocytes because it has antioxidant effect. Treatment with 3,7-DMF induced antioxidant genes, quenches ROS away, and improved the hepatocyte condition that was impaired by H2O2 as reflected by restoration of HNF-4α and albumin. In the TAA-mouse liver injury model also, TAA significantly increased ROS in the liver which led to decrease of albumin and nuclear expression of HNF-4α, increase of TGF-ß1 and hepatocytes death, accumulation of lipid, and extra-nuclear localization of HMGB1. Treatment of 3,7-DMF normalized all these pathologic findings and prevented or resolved liver fibrosis. In conclusion, we discovered 3,7-DMF that inhibits liver fibrosis based on dual actions; antioxidant and inhibitor of TGF-ß1-induced activation of HSCs.

Asunto(s)

Antioxidantes , Células Estrelladas Hepáticas , Ratones , Animales , Humanos , Células Estrelladas Hepáticas/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/genética , Hígado/metabolismo , Modelos Animales de Enfermedad

RESUMEN

Black ginger is used as an herbal medicine for self-care and health promotion. Black ginger extract has been shown to alter the function of transporters in several cell types. This study demonstrates the interaction between the extract and 5,7-dimethoxyflavone (DMF) on drug efflux mediated by breast cancer resistance proteins (BCRP) and P-glycoprotein (P-gp) in Caco-2 cells and heterologous cell systems [Madin-Darby canine kidney type II (MDCKII) stably transfected with human BCRP (MDCKII/BCRP) or human P-gp (MDCKII/P-gp)]. The transepithelial flux of 3H-Digoxin and 3H-Estrone sulfate, prototypic substrates of P-gp, and BCRP, respectively, across Caco-2 cell monolayers, MDCKII/BCRP, and MDCKII/P-gp cells were determined. The results demonstrate that black ginger extract (10 µg/ml) significantly increases 3H-Digoxin and 3H-Estrone sulfate transport from the apical to basolateral side while decreasing transport from the basolateral to apical side of Caco-2 cells and MDCKII cell overexpression of BCRP or P-gp. The effect of the extract on 3H-Digoxin and 3H-Estrone sulfate transport was related to a decrease in efflux ratio. Likewise, DMF (5 µM) significantly increased 3H-Digoxin and 3H-Estrone sulfate absorption with a decreased efflux ratio compared to the control. Interestingly, the extract also significantly increased absorption of paclitaxel, an anti-cancer drug, which has poor oral absorption. Taken together, co-administration of drugs as substrates of BCRP and P-gp, with the black ginger extract containing DMF, might alter the pharmacokinetic profiles of the medicine.

Asunto(s)

Absorción Intestinal , Proteínas de Neoplasias , Animales , Perros , Humanos , Preparaciones Farmacéuticas , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Células CACO-2 , Proteínas de Neoplasias/metabolismo , Transporte Biológico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Digoxina/farmacocinética

RESUMEN

The genus Daphnopsis has been traditionally used as a purgative, diuretic, stimulant, and psoriasis treatment. In this study, the anti-AD (atopic dermatitis) activities of the Daphnopsis costaricensis EtOH extract (DCE) were investigated in an oxazolone (OX)-induced mouse model of AD, and the anti-inflammatory effects of its active compounds were confirmed in PI-sensitized or IgE/DNP-BSA-sensitized RBL-2H3 cells. DCE improved the symptoms of OX-induced inflammatory dermatitis (swelling, erythema, and increased ear thickening) in OX-induced BALB/c mice ears and reduced epidermal thickness and mast cell infiltration. Eleven flavonoid compounds were isolated from DCE, and two compounds (7,8-dimethoxyflavone and 7,2'-dimethoxyflavone) significantly inhibited IL-4 overexpression in PI-induced RBL-2H3 cells and mast cell degranulation in IgE + DNP-BSA-induced RBL-2H3 cells. Our study indicates that DCE and two compounds (7,8-dimethoxyflavone and 7,2'-dimethoxyflavone) might effectively improve inflammatory and atopic skin symptoms.

Asunto(s)

Dermatitis Atópica , Thymelaeaceae , Ratones , Animales , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Oxazolona/toxicidad , Ratones Endogámicos BALB C , Dinitroclorobenceno/efectos adversos , Extractos Vegetales/efectos adversos , Inmunoglobulina E , Mastocitos , Citocinas , Piel

RESUMEN

Kaempferia parviflora (KP) extract has recently attracted attention in Japan as a dietary supplement; however, there is little information regarding food-drug interactions (FDIs). The current study was conducted to clarify the FDI of KP extract via inhibition of cytochrome P450 3A (CYP3A), a typical drug-metabolizing enzyme. The inhibitory effects of KP extract and its main ingredients, 5,7-dimethoxyflavone (5,7-DMF) and 3,5,7,3',4'-pentamethoxyflavone (3,5,7,3',4'-PMF), on CYP3A-mediated midazolam 1'-hydroxylation (MDZ 1'-OH) activity were investigated in human liver microsomes. In addition, the effect of a single oral treatment with KP extract (135 mg/kg) on oral MDZ (15 mg/kg) metabolism was investigated in rats. Serum MDZ concentration was analyzed and pharmacokinetic parameters were compared with the control group. KP extract competitively inhibited MDZ 1'-OH activity with an inhibition constant value of 78.14 µg/ml, which was lower than the estimated concentration in the small intestine after ingestion. Furthermore, KP extract, 5,7-DMF, and 3,5,7,3',4'-PMF inhibited the activity in a time-, NADPH-, and concentration-dependent manner. In vivo study showed that administration of KP extract to rats 2 h before MDZ significantly increased the area under the serum concentration-time curve and the maximum concentration of MDZ significantly by 2.3- and 1.9- fold, respectively (p < 0.05). Conversely, administration of MDZ 18 h after KP extract treatment displayed a weaker effect. These results suggest that KP extract competitively inhibits CYP3A-mediated MDZ metabolism, and that this inhibition may be time-dependent but not irreversible. This work suggests an FDI through CYP3A inhibition by KP extract.

RESUMEN

Oxidation of 3'-methoxyflavone, 4'-methoxyflavone, and 3',4'-dimethoxyflavone and their derivatives containing 5,7-dihydroxyl groups by human cytochrome P450 (P450 or CYP) 1B1 and 2A13 was determined using LC-MS/MS systems.3'-Methoxyflavone and 4'-methoxyflavone were mainly O-demethylated to form 3'-hydroxyflavone and 4'-hydroxyflavone, respectively, and then 3',4'-dihydroxyflavone at higher rates with CYP1B1 than with CYP2A13. 4'-Methoxy-5,7-dihydroxyflavone (acacetin) was found to be demethylated by CYP1B1 and 2A13 to form 4',5,7-trihydroxyflavone (apigenin) at rates of 0.098-1 and 0.42 min-1, respectively. 3'-Methoxy-5,7-dihydroxyflavone was also demethylated by both P450s, with CYP2A13 being more active.3',4'-Dimethoxyflavone was a good substrate for CYP1B1 but not for CYP2A13 and was found to be mainly O-demethylated to form 3',4'-dihydroxyflavone (at a rate of 4.2 min-1) and also several ring-oxygenated products having m/z 299 fragments. Molecular docking analysis supported the proper orientation for formation of these products by CYP1B1.Our present results showed that 3'- and 4'-methoxyflavone can be oxidised to their O-demethylated products and, to a lesser extent, to ring oxidation products by both P450s 1B1 and 2A13 and that 3',4'-dimethoxyflavone is a good substrate for CYP1B1 in forming both O-demethylated and ring-oxidation products. Introduction of a 57diOHF moiety into these methoxylated flavonoids caused decreased in oxidation by CYP1B1 and 2A13.

Asunto(s)

Flavonoides , Espectrometría de Masas en Tándem , Cromatografía Liquida , Citocromo P-450 CYP1B1 , Sistema Enzimático del Citocromo P-450 , Flavonas , Flavonoides/química , Humanos , Simulación del Acoplamiento Molecular

RESUMEN

Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.

RESUMEN

5,7-Dimethoxyflavone, a chrysin derivative, occurs in many plants and shows very low toxicity, even at high doses. On the basis of this phenomenon, we biotransformed a series of methoxy-derivatives of chrysin, apigenin, and tricetin obtained by chemical synthesis. We used entomopathogenic fungal strains with the confirmed ability of simultaneous hydroxylation/demethylation and glycosylation of flavonoid compounds. Both the amount and the place of attachment of the methoxy group influenced the biotransformation rate and the product's amount nascent. Based on product and semi-product structures, it can be concluded that they are the result of cascading transformations. Only in the case of 5,7,3',4',5'-pentamethoxyflavone, the strains were able to attach a sugar molecule in place of the methoxy substituent to give 3'-O-ß-d-(4″-O-methylglucopyranosyl)-5,7,4',5'-tetramethoxyflavone. However, we observed the tested strains' ability to selectively demethylate/hydroxylate the carbon C-3' and C-4' of ring B of the substrates used. The structures of four hydroxyl-derivatives were determined: 4'-hydroxy-5,7-dimethoxyflavone, 3'-hydroxy-5,7-dimethoxyflavone, 3'-hydroxy-5,7,4',5'-tetramethoxyflavone, and 5,7-dimethoxy-3',4'-dihydroxyflavone (5,7-dimethoxy-luteolin).

Asunto(s)

Flavonoides , Hongos , Biotransformación , Flavonas , Hidroxilación , Luteolina

RESUMEN

The cardiac action potential is regulated by several ion channels. Drugs capable to block these channels, in particular the human ether-à-go-go-related gene (hERG) channel, also known as KV11.1 channel, may lead to a potentially lethal ventricular tachyarrhythmia called "Torsades de Pointes". Thus, evaluation of the hERG channel off-target activity of novel chemical entities is nowadays required to safeguard patients as well as to avoid attrition in drug development. Flavonoids, a large class of natural compounds abundantly present in food, beverages, herbal medicines, and dietary food supplements, generally escape this assessment, though consumed in consistent amounts. Continuously growing evidence indicates that these compounds may interact with the hERG channel and block it. The present review, by examining numerous studies, summarizes the state-of-the-art in this field, describing the most significant examples of direct and indirect inhibition of the hERG channel current operated by flavonoids. A description of the molecular interactions between a few of these natural molecules and the Rattus norvegicus channel protein, achieved by an in silico approach, is also presented.

Asunto(s)

Canal de Potasio ERG1/antagonistas & inhibidores , Flavonoides/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos , Bloqueadores de los Canales de Potasio/toxicidad , Torsades de Pointes/inducido químicamente , Potenciales de Acción , Animales , Canal de Potasio ERG1/química , Canal de Potasio ERG1/metabolismo , Humanos , Síndrome de QT Prolongado/metabolismo , Síndrome de QT Prolongado/fisiopatología , Miocitos Cardíacos/metabolismo , Conformación Proteica , Medición de Riesgo , Factores de Riesgo , Relación Estructura-Actividad , Torsades de Pointes/metabolismo , Torsades de Pointes/fisiopatología

RESUMEN

Sarcopenia is a muscle disease featured by the loss of muscle mass and dysfunction with advancing age. The 5,7-dimethoxyflavone (DMF), a major flavone found in Kaempferia parviflora, has biological activities, including anti-diabetes, anti-obesity, and anti-inflammation. However, its anti-sarcopenic effect remains to be elucidated. This current study investigated the inhibitory activity of DMF on sarcopenia. Eighteen-month-old mice were orally administered DMF at the dose of 25 mg·kg-1·day-1 or 50 mg·kg-1·day-1 for 8 weeks. DMF not only stimulated grip strength and exercise endurance but also increased muscle mass and volume. Besides, DMF stimulated the phosphatidylinositol 3-kinase-Akt pathway, consequently activating the mammalian target of rapamycin-eukaryotic initiation factor 4E-binding protein 1-70-kDa ribosomal protein S6 kinase pathway for protein synthesis. DMF reduced the mRNA expression of E3 ubiquitin ligase- and autophagy-lysosomal-related genes involved in proteolysis via the phosphorylation of Forkhead box O3. DMF upregulated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, nuclear respiratory factor 1, and mitochondrial transcription factor A along with the increase of relative mitochondrial DNA content. DMF alleviated inflammatory responses by reducing the tumor necrosis factor-alpha and interleukin-6 serum and mRNA levels. Collectively, DMF can be used as a natural agent to inhibit sarcopenia via improving protein turnover and mitochondria function.

Asunto(s)

Flavonoides/administración & dosificación , Flavonoides/farmacología , Proteínas Musculares/metabolismo , Biogénesis de Organelos , Fitoterapia , Sarcopenia/tratamiento farmacológico , Sarcopenia/metabolismo , Administración Oral , Animales , Índice de Masa Corporal , Flavonoides/aislamiento & purificación , Inflamación , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sarcopenia/fisiopatología , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo , Zingiberaceae/química

RESUMEN

Endometriosis is a reproductive disorder characterized by the dislocation of endometrial tissues. Approximately 5-20% of women at their reproductive age are diagnosed with endometriosis, which causes chronic pain and infertility. Here, we demonstrated that the bioactive flavonoid, 5,7-dimethoxyflavone (DMF), exhibited antiproliferative and apoptotic effects in VK2/E6E7 and End1/E6E7 cells which were established from vaginal and endocervical tissue taken from a premenopausal woman undergoing hysterectomy for endometriosis. DMF treatment significantly elevated DNA fragmentation resulting in apoptotic cell death in both cell lines. Furthermore, DMF induced loss of mitochondrial membrane potential, dysregulation of intracellular calcium level, and ROS production, which accelerate apoptosis. Additionally, DMF modulated the expression of the signaling molecules related to cell survival and endoplasmic reticulum stress in VK2/E6E7 and End1/E6E7 cells. Overall, DMF may ameliorate endometriosis and can be a potential alternative to hormonal and surgical therapy for endometriosis treatment.

Asunto(s)

Apoptosis/efectos de los fármacos , Endometriosis/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Flavonoides/farmacología , Flavonoides/uso terapéutico , Humanos

RESUMEN

Objective: To investigate the chemical constituents from the whole plants of Scutellaria viscidula. Methods: By means of preparative HPTLC and column chromatography over silica gel and Sephadex LH-20, the chemical constituents were isolated and purified. Their structures were elucidated by physico-chemical properties and spectral analyses. Results: A total of 22 compounds were isolated and identified as: 5-hydroxy-7,8-dimethoxyflavone (1), chrysin (2), 5,7-dimethoxyflavone (3), 5,7,4’-trihydroxy- 6-methoxyflavone (4), 5,7,4’-trihydroxyflavonoid (5), 5,7,2’-trihydroxy-8-methoxyflavone (6), 5,7-dihydroxy-8,2’-dimethoxyflavone (7), 5,7,2’-trihydroxy-6-methoxyflavanone (8), 5-hydroxy-6,7,8-trimethoxyflavone (9), 5,6,7-trimethoxyflavone (10), 3,5-dimethoxy- 6,7-methylenedioxyflavone (11), 5,2’-dihydroxy-7,8,6’-trimethoxyflavone (12), 5,2’-dihydroxy-7,8,6’-trimethoxyflavanone (13), 5,7-dimethoxyflavanone (14), 7-methoxy-chrysin (15), 2’-hydroxy-5,7,8-trimethoxyflavone (16), ferulic acid (17), 4-hydroxy-3- methoxybenzoic acid (18), p-hydroxy-benzaldehyde (19), 3,5-dimethoxy-4-hydroxybenzoic acid (20), 7-hydroxy-6-methoxy-coumarin (21), 6,7-dihydroxyl-coumarin (22). Conclusion: Compounds 1, 3-16, 18 and 20 are isolated from Scutellaria viscidula for the first time.

RESUMEN

OBJECTIVES: Crude extracts of Dodonaea viscosa var. angustifolia (DVA), has shown to have anticariogenic property. However the compound responsible for this activity has not been identified. The aim of this study was to investigate anti-acidogenic and anti-biofilm activity of a flavone 5,6,8-Trihydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one isolated from D. viscosa var. angustifolia (DVA) in cariogenic bacteria Streptococcus mutans. METHODS: The crude extract from DVA leaves was fractionated into six fractions (F1-F6) using chromatography. The Minimum Inhibitory Concentrations (MIC) and Minimum Bactericidal Concentration (MBC) were determined. The effect of the six fractions on biofilm formation and acid production were investigated. The most active fraction (F5) was further fractionated, purified, identified and elucidated using GC-MS and NMR. The anticariogenic property of this purified compound was established. Results were analyzed using Wilcoxon rank-sum test (Mann-Whitney). RESULTS: The MIC and MBC of the fractions (F1-F6) and crude extract ranged from 0.39 to 12.5 mg/ml. F5 showed the lowest MBC. At 0.2 mg/ml, F5 reduced biofilm formation by 93.3% and reduced acid production in S. mutans. Subfraction F5.1 showed higher antimicrobial activity compared to the crude extract and F5. Purified F5.1 was identified as 5,6,8-Trihydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one (TMMC). TMMC inhibited biofilm formation at both 6 h (94% reduction) and 24 h (99% reduction), which was higher compared to the crude extract (87% reduction at 0.78 mg/ml after 6 h). TMMC also exhibited a higher inhibitory effect on acid production compared to the crude extract. CONCLUSION: Flavone 5,6,8-Trihydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one derived from DVA has anti-S. mutans, anti-biofilm and anti-acidogenic activity therefore it has a potential for use in the oral cavity to prevent dental caries.

Asunto(s)

Antibacterianos/química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Sapindaceae/química , Ácidos/metabolismo , Antibacterianos/aislamiento & purificación , Biopelículas/crecimiento & desarrollo , Caries Dental/microbiología , Caries Dental/prevención & control , Flavonas/química , Flavonas/farmacología , Pruebas de Sensibilidad Microbiana , Hojas de la Planta/química , Sudáfrica , Streptococcus mutans/efectos de los fármacos

RESUMEN

Arterial hypertension is one of the main risk factors in the development of cardiovascular diseases. Therefore, it is important to look for new drugs to treat hypertension. In this study, we carried out the screening of 19 compounds (triterpenes, diterpenes, sesquiterpenes, lignans, and flavonoids) isolated from 10 plants used in Mexican traditional medicine to determine whether they elicited vascular smooth muscle relaxation and, therefore, could represent novel anti-hypertension drug candidates. The vasorelaxant activity of these compounds was evaluated on the isolated rat aorta assay and the results obtained from this evaluation showed that three compounds induced a significant vasodilatory effect: meso-dihydroguaiaretic acid [half maximal effective concentration (EC50), 49.9 ± 11.2 µM; maximum effect (Emax), 99.8 ± 2.7%]; corosolic acid (EC50, 108.9 ± 6.7 µM; Emax, 96.4 ± 4.2%); and 5,8,4'-trihydroxy-3,7-dimethoxyflavone (EC50, 122.3 ± 7.6 µM; Emax, 99.5 ± 5.4%). Subsequently, involvement of the NO/cyclic guanosine monophosphate (cGMP) and H2S/ATP-sensitive potassium channel (KATP) pathways on the vasodilator activity of these compounds was assessed. The results derived from this analysis showed that the activation of both pathways contributes to the vasorelaxant effect of corosolic acid. On the other hand, the vasodilator effect of meso-dihydroguaiaretic acid and 5,8,4'-trihydroxy-3,7-dimethoxyflavone, partly involves stimulation of the NO/cGMP pathway. However, these compounds also showed an important endothelium-independent vasorelaxant effect, whose mechanism of action remains to be clarified. This study indicates that meso-dihydroguaiaretic acid, corosolic acid, and 5,8,4'-trihydroxy-3,7-dimethoxyflavone could be used as lead compounds for the synthesis of new derivatives with a higher potency to be developed as drugs for the prevention and treatment of cardiovascular diseases.

Asunto(s)

Músculo Liso/irrigación sanguínea , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Plantas/química , Vasodilatadores/aislamiento & purificación , Vasodilatadores/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiología , GMP Cíclico/metabolismo , Flavonoides/química , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Lignanos/química , Lignanos/aislamiento & purificación , Lignanos/farmacología , Medicina Tradicional , México , Estructura Molecular , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Extractos Vegetales/química , Ratas , Terpenos/química , Terpenos/aislamiento & purificación , Terpenos/farmacología , Vasodilatación , Vasodilatadores/química

RESUMEN

5,7-Dimethoxyflavone (5,7-DMF), one of the major components of Kaempferia parviflora, has anti-obesity, anti-inflammatory, and antineoplastic effects. On the other hand, in vitro studies have reported that it directly inhibits the drug metabolizing enzyme family cytochrome P450 (CYP) 3As. In this study, its safety was evaluated from a pharmacokinetic point of view, based on daily ingestion of 5,7-DMF. Midazolam, a substrate of CYP3As, was orally administered to mice treated with 5,7-DMF for 10 days, and its pharmacokinetic properties were investigated. In the group administered 5,7-DMF, the area under the curve (AUC) of midazolam increased by 130% and its biological half-life was extended by approximately 100 min compared to the control group. Compared to the control group, 5,7-DMF markedly decreased the expression of CYP3A11 and CYP3A25 in the liver. These results suggest that continued ingestion of 5,7-DMF decreases the expression of CYP3As in the liver, consequently increasing the blood concentrations of drugs metabolized by CYP3As.

Asunto(s)

Flavonoides/uso terapéutico , Midazolam/uso terapéutico , Animales , Flavonoides/farmacología , Humanos , Masculino , Ratones , Midazolam/farmacocinética

RESUMEN

Kaempferia parviflora Wall. ex Baker is a medicinal plant found in the upper Northeastern regions of Thailand, which belongs to Zingiberaceae family. The present study aims to investigate the standardization parameters, to analyze chemical constituents of volatile oil by gas chromatography-mass spectrometry, and to determine the content of 5,7-dimethoxyflavone in K. parviflora rhizomes by thin-layer chromatography (TLC)-densitometry compared to TLC image analysis. K. parviflora rhizomes from 15 different sources throughout Thailand were investigated for morphological and pharmacognostic parameters. 5,7-Dimethoxyflavone contents were determined by TLC-densitometry with winCATS software and TLC image analysis with ImageJ software. The mobile phase for TLC development consisted of toluene: chloroform: Acetone: formic acid (5: 4: 1: 0.2). For the Results, the pharmacognostic parameters of K. parviflora rhizome were demonstrated. The loss on drying, total ash, acid-insoluble ash, water content, volatile oil content, ethanol, and water-soluble extractive values were found to be 8.979 ± 0.041, 5.127 ± 0.060, 2.174 ± 0.092, 9.291 ± 0.458, 0.028 ± 0.003, 5.138 ± 0.092, and 8.254 ± 0.191 g/100 g of dry weight, respectively. K. parviflora volatile oil showed the major components of α-copaene, dauca-5, 8-diene, camphene, ß-pinene, borneol, and linalool. The 5,7-dimethoxyflavone content of K. parviflora rhizomes determined by TLC-densitometry and TLC image analysis were found to be 2.15 ± 0.64 and 1.96 ± 0.51 g/100 g of dry rhizomes, respectively. The 5,7-dimethoxyflavone contents of both methods were not significantly different (P > 0.05) using paired t-test.

RESUMEN

Tyrosine kinase inhibitors (TKI) are a novel and target-specific class of anticancer drugs. One drawback of TKI therapy is cancer resistance to TKI. An important TKI resistance mechanism is enhanced efflux of TKI by efflux transporters, such as Breast Cancer Resistance Protein (BCRP), in cancer cells. 5,7-Dimethoxyflavone (5,7-DMF) is a natural flavonoid which was recently reported to be a potent BCRP inhibitor. In the current study, the effect of 5,7-DMF on the disposition of sorafenib, a TKI which is a good substrate of BCRP, was investigated both in vitro in efflux transporter expressing cells and in vivo in mice. 5,7-DMF significantly inhibited Bcrp1-mediated sorafenib efflux in a concentration dependent manner in MDCK/Bcrp1 cells, with EC50 value of 8.78 µM. The pharmacokinetics and tissue distribution of sorafenib (10 mg/kg) with and without co-administration of 75 mg/kg 5,7-DMF were determined. With 5,7-DMF, the AUC of sorafenib in plasma was 47,400 ±â€¯4790 ng·h/mL, which was significantly higher than 27,300 ±â€¯2650 ng·h/mL in sorafenib alone group. In addition, compared to sorafenib alone group, great increase in sorafenib AUC was observed in most tissues collected when sorafenib was given with 5,7-DMF. Our results indicated that 5,7-DMF may represent a novel and very promising chemosensitizing agent for BCRP-mediated anticancer drug resistance due to its low toxicity and potent BCRP inhibition.

Asunto(s)

Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Antineoplásicos/farmacocinética , Flavonoides/farmacología , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacología , Transporte Biológico , Perros , Interacciones Farmacológicas , Resistencia a Antineoplásicos , Células LLC-PK1 , Células de Riñón Canino Madin Darby , Masculino , Ratones , Niacinamida/sangre , Niacinamida/farmacocinética , Niacinamida/farmacología , Compuestos de Fenilurea/sangre , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacología , Sorafenib , Porcinos , Distribución Tisular

RESUMEN

BACKGROUND: Flavonoids are considered potential anticancer agents owing to their properties to interact with a diversity of cellular entities. Among flavonoids, methylated flavones are more efficient anticancer agents due to their higher stability in vivo. The purpose of the present study was, therefore, to evaluate the anticancer effect of methylated natural flavonoid 5, 7-dimethoxyflavone (5, 7-DMF). MATERIALS AND METHODS: MTT assay was used to determine the anticancer activity and IC50 of 5, -DMF). Cell viability, cell cycle distribution, reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were carried out by flow cytometry. Apoptosis was studied by DAPI staining. RESULTS: MTT assay revealed that the molecule reduced the cell viability of HepG2 cancer cells. The IC50 of 5, 7-DMF was found to be 25 µM. Our result indicated that 5, 7-DMF triggered production of ROS and significantly reduced ΔΨm . It also leads to arrest of HepG2 cells in Sub-G1 stage of cell cycle, and ultimately induced apoptosis in a concentration-dependent manner, as indicated by DAPI staging. Additionally, 5, 7-DMF also reduced the colony forming potential of the HepG2 cells concentration dependently. CONCLUSION: Taken together, we conclude that 5, 7-DMF induces cell death via ROS generation, cell cycle arrest and apoptosis, and, therefore, may prove beneficial in the treatment of liver cancer.

Asunto(s)

Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Flavonoides/farmacología , Neoplasias Hepáticas/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo