RESUMEN

Puerarin has been reported to have anticancer properties; however, its mechanism in regulating triple-negative breast cancer (TNBC) remains unclear. Cell function was assessed using a cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, and transwell assay. Additionally, the glucose assay kit, lactate assay kit, and ADP/ATP ratio assay kit were used to analyze glucose metabolism. mRNA and protein expression levels were analyzed using qRT-PCR and western blotting assays, respectively. The relationship between FUS RNA binding protein (FUS) and mitogen-activated protein kinase 4 (MAPK4) was determined using an RNA immunoprecipitation assay. TNBC cell malignancy in vitro was validated using a xenograft mouse model assay. Puerarin treatment or MAPK4 knockdown effectively inhibited TNBC cell proliferation, invasion, and glucose metabolism, and induced cell apoptosis. Additionally, puerarin treatment downregulated MAPK4 and FUS expression. Conversely, MAPK4 overexpression attenuated the effects of puerarin in TNBC cells. FUS stabilized MAPK4 mRNA expression in TNBC cells. Furthermore, puerarin decreased MAPK4 expression by downregulating FUS in TNBC cells. Finally, puerarin inhibited tumor formation in vivo. Puerarin inhibited TNBC development by decreasing the expression of FUS-dependent MAPK4, indicating that puerarin may serve as a promising therapeutic agent to hind TNBC.

Asunto(s)

Proliferación Celular , Isoflavonas , Proteína FUS de Unión a ARN , Neoplasias de la Mama Triple Negativas , Isoflavonas/farmacología , Isoflavonas/química , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Humanos , Animales , Femenino , Línea Celular Tumoral , Ratones , Proliferación Celular/efectos de los fármacos , Proteína FUS de Unión a ARN/metabolismo , Proteína FUS de Unión a ARN/genética , Apoptosis/efectos de los fármacos , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/química

RESUMEN

Multidrug resistance (MDR) remains the most difficult problem facing conventional chemotherapy for cancers. Astragalus membranaceus is a historically traditional Chinese medicine. One of its bioactive components, formononetin, exhibits antitumor effects on various cancers. However, the effects of formononetin on MDR cancers have not been evaluated. Therefore, we investigated the defense's effects of formononetin on MDR. We used rhodamine 123 and doxorubicin efflux assays to analyze the inhibition kinetics of P-glycoprotein (P-gp) mediated-efflux. Cell viability was detected by sulforhodamine B assay, and the synergistic effects of formononetin combined with chemotherapeutic agents were further calculated using CompuSyn software. Molecular docking was performed with iGEMDOCK. We discovered that formononetin considerably induced oxidative stress and the disruption of mitochondrial membrane potential in MDR cancer cells. Furthermore, formononetin inhibits the P-gp efflux function by ATPase stimulation and the uncompetitive inhibition of P-gp-mediated effluxes of rhodamine 123 and doxorubicin. The molecular docking model indicates that formononetin may bind to P-gp by strong hydrogen bonds at Arginine (Arg) 489 and Glutamine (Gln) 912. Formononetin exhibits significant synergistic effects with vincristine and doxorubicin toward MDR cancer cells, and it synergistically suppressed tumor growth in vivo with paclitaxel. These results suggest that formononetin should be seen as a potential candidate for the adjuvant therapy of MDR cancers.

Asunto(s)

Doxorrubicina , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Isoflavonas , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Isoflavonas/farmacología , Isoflavonas/química , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Estrés Oxidativo/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Ratones , Doxorrubicina/farmacología , Línea Celular Tumoral , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Supervivencia Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Sinergismo Farmacológico

RESUMEN

This study compared the nutritional components, isoflavones, and antioxidant activities by solid-sate fermentation of Apios americana Medikus (AAM) with seven different fungi. The total fatty acid contents increased from 120.5 mg/100 g (unfermented AAM, UFAAM) to 242.0 to 3167.5 mg/100 g (fermented AAM, FAAM) with all fungi. In particular, the values of total fatty acids were highest (26.3-fold increase) in the FAAM with Monascus purpureus. The amount of total free amino acids increased from 591.69 mg/100 g (UFAAM) to 664.38 to 1603.07 mg/100 g after fermentation except for Monascus pilosus and Lentinula edodes. The total mineral contents increased evidently after fermentation with M. purpureus, F. velutipes, and Tricholoma matsutake (347.36 â†’ 588.29, 576.59, and 453.32 mg/100 g, respectively). The UFAAM predominated isoflavone glycosides, whereas glycoside forms were converted into aglycone forms after fermentation by fungi. The bioconversion rates of glycoside to aglycone were excellent in the FAAM with M. pilosus, M. purpureus, F. velutipes, and T. matsutake (0.01 â†’ 0.69, 0.50, 0.27, and 0.31 mg/g, respectively). Furthermore, the total phenolic contents, total flavonoid contents, and antioxidant activities by the abovementioned FAAM were high except for L.edodes. This FAAM can be used as a potential food and pharmaceutical materials.

Asunto(s)

Antioxidantes , Fermentación , Hongos , Antioxidantes/metabolismo , Antioxidantes/química , Hongos/metabolismo , Ácidos Grasos/metabolismo , Ácidos Grasos/química , Metabolismo Secundario , Isoflavonas/metabolismo , Isoflavonas/análisis , Isoflavonas/química , Monascus/metabolismo , Monascus/química , Monascus/crecimiento & desarrollo , Aminoácidos/metabolismo , Aminoácidos/análisis

RESUMEN

Although formononetin has a considerable biological activity, its therapeutic use is limited by its low solubility. Formononetin was dissolved in ethanol, methanol, N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) in this investigation, the antisolvent precipitation procedure with the assistance of an external ultrasonic probe was used to manufacture the formononetin nano-particles. The ideal parameters for response surface BBD optimization are as follows: feed volume flow rate of 6 mL/min; ultrasonic power of 860 W; and liquid-liquid ratio of 1:12.5. The formononetin nano-particles have a smaller particle diameter than raw sample; the lowest size can be as small as (329 ± 1.99) nm, which is 45 times smaller than raw. An in vitro digestion test using a solution that simulated intestinal solution revealed that the release rate of the nano-particle was 1.75 times than that of the raw formononetin. The formononetin nano-particles generated by the aforementioned four solvents have the following order of diameter: ethanol > methanol > DMF > DMSO. This study provided a technical reference for the functional food components in deep processing.

Asunto(s)

Isoflavonas , Nanopartículas , Tamaño de la Partícula , Solventes , Isoflavonas/química , Nanopartículas/química , Solventes/química , Solubilidad , Precipitación Química , Ultrasonido

RESUMEN

Pre-eclampsia (PE) is classified as pregnancy-specific hypertensive disease and responsible for severe fetal and maternal morbidity and mortality, which influenced an approximate 3 âˆ¼ 8 % of all pregnancies in both developed and developing countries. However, the exact pathological mechanism underlying PE has not been elucidated and it is urgent to find innovate pharmacotherapeutic agents for PE. Recent studies have reported that a crucial part of the etiology of PE is played by placental oxidative stress. Therefore, to treat PE, a possible treatment approach is to mitigate the placental oxidative stress. Alpinumisoflavone (AIF) is a prenylated isoflavonoid originated in mandarin melon berry called Cudrania tricuspidate, and is well known for its versatile pharmacotherapeutic properties, including anti-fibrotic, anti-inflammatory, anti-tumor, and antioxidant activity. However, protective property of AIF on extravillous trophoblast (EVT) under placental oxidative stress has not been elucidated yet. Therefore, we assessed stimulatory effects of AIF on the viability, invasion, migration, mitochondria function in the representative EVT cell line, HTR-8/SVneo cell. Moreover, protective activities of AIF from H2O2 were confirmed, in terms of reduction in apoptosis, ROS production, and depolarization of mitochondrial membrane. Furthermore, we confirmed the direct interaction of AIF with sirtuin1 (SIRT1) using molecular docking analysis and SIRT1-mediated signaling pathways associated with the protective effects of AIF on HTR-8/SVneo cells under oxidative stress. Finally, beneficial efficacy of AIF against oxidative stress was further confirmed using BeWo cells, syncytiotrophoblast cell lines. These results suggest that AIF may ameliorate H2O2-induced intracellular damages through SIRT1 activation in human trophoblast cells.

Asunto(s)

Peróxido de Hidrógeno , Isoflavonas , Preeclampsia , Sirtuina 1 , Sirtuina 1/metabolismo , Humanos , Isoflavonas/farmacología , Isoflavonas/química , Isoflavonas/aislamiento & purificación , Preeclampsia/tratamiento farmacológico , Preeclampsia/metabolismo , Preeclampsia/patología , Femenino , Peróxido de Hidrógeno/farmacología , Embarazo , Estructura Molecular , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-Actividad , Apoptosis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Células Cultivadas

RESUMEN

The bactericidal properties of traditional food coatings mostly depend on the amount of fungicides present, which reduces the sustainability of food packaging. Herein, we proposed a magnetic field to precisely modulate the near-infrared (NIR) absorption activity to enhance antimicrobial coatings sustainability. Inspired by the typical grinding procedure, the assembly of CP/Fe3O4@TA nanofiber hydrogel was proposed as the coating, applying mechanical force and encouraging the collision of effective molecules of puerarin (PUE), chitosan (CS), and Fe3O4@TA NFs. This hydrogel design offers precise control over the physical and chemical properties, including appearance, viscoelasticity, and rheology. Particularly, significant changes in photothermal performance were observed as a result of magnetic regulation of NIR absorption activity. As a result, the CP/Fe3O4@TA coatings achieve effective bacteria killing performance under NIR irradiation, magnetocaloric effect, boric acid adsorption, and aggregation interference. Finally, the hydrogel coating was applied to the beef surface and serves as an effective barrier against the growth of pathogenic bacteria, thereby preserving the freshness and tenderness of the beef. The finding from this work is expected to open up a new way in active nano hydrogel coating for food preservation.

Asunto(s)

Quitosano , Hidrogeles , Quitosano/química , Quitosano/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Animales , Bovinos , Isoflavonas/química , Isoflavonas/farmacología , Conservación de Alimentos/métodos , Antiinfecciosos/farmacología , Antiinfecciosos/química , Carne Roja , Antibacterianos/farmacología , Antibacterianos/química

RESUMEN

Purpose: Mitochondrial damage may lead to uncontrolled oxidative stress and massive apoptosis, and thus plays a pivotal role in the pathological processes of myocardial ischemia-reperfusion (I/R) injury. However, it is difficult for the drugs such as puerarin (PUE) to reach the mitochondrial lesion due to lack of targeting ability, which seriously affects the expected efficacy of drug therapy for myocardial I/R injury. Methods: We prepared triphenylphosphonium (TPP) cations and ischemic myocardium-targeting peptide (IMTP) co-modified puerarin-loaded liposomes (PUE@T/I-L), which effectively deliver the drug to mitochondria and improve the effectiveness of PUE in reducing myocardial I/R injury. Results: In vitro test results showed that PUE@T/I-L had sustained release and excellent hemocompatibility. Fluorescence test results showed that TPP cations and IMTP double-modified liposomes (T/I-L) enhanced the intracellular uptake, escaped lysosomal capture and promoted drug targeting into the mitochondria. Notably, PUE@T/I-L inhibited the opening of the mitochondrial permeability transition pore, reduced intracellular reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) levels, thereby decreasing the percentage of Hoechst-positive cells and improving the survival of hypoxia-reoxygenated (H/R)-injured H9c2 cells. In a mouse myocardial I/R injury model, PUE@T/I-L showed a significant myocardial protective effect against myocardial I/R injury by protecting mitochondrial integrity, reducing myocardial apoptosis and decreasing infarct size. Conclusion: This drug delivery system exhibited excellent mitochondrial targeting and reduction of myocardial apoptosis, which endowed it with good potential extension value in the precise treatment of myocardial I/R injury.

Asunto(s)

Isoflavonas , Liposomas , Daño por Reperfusión Miocárdica , Compuestos Organofosforados , Animales , Liposomas/química , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Isoflavonas/química , Isoflavonas/farmacología , Isoflavonas/administración & dosificación , Isoflavonas/farmacocinética , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/farmacocinética , Masculino , Ratones , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Cationes/química , Miocardio/patología , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos

RESUMEN

Flavin-dependent monooxygenases (FMOs) are a valuable group of biocatalysts that can regioselectively introduce a hydroxy group for the targeted modification of biologically active compounds. Here, we present the fdeE, the FMO from Herbaspirillum seropedicae SmR1 that is a part of the naringenin degradation pathway and is active towards a wide range of flavonoids-flavanones, flavones, isoflavones, and flavonols. Bioinformatics and biochemical analysis revealed a high similarity between the analyzed enzyme and other F8H FMOs what might indicate convergent evolutionary mechanism of flavonoid degradation pathway emergence by microorganism. A simple approach with the manipulation of the reaction environment allowed the stable formation of hydroxylation products, which showed very high reactivity in both in vivo and in vitro assays. This approach resulted in an 8-hydroxyquercetin-gossypetin titer of 0.16 g/L and additionally it is a first report of production of this compound.

Asunto(s)

Flavonoles , Isoflavonas , Isoflavonas/metabolismo , Isoflavonas/química , Isoflavonas/biosíntesis , Flavonoles/metabolismo , Flavonoides/metabolismo , Flavonoides/química , Flavonoides/biosíntesis , Hidroxilación , Especificidad por Sustrato

RESUMEN

Soybeans' isoflavone content increases with germination; nevertheless, their bioaccessibility in the gastrointestinal system is limited. This study evaluated the influence of germination time (1, 3, 5, and 7 days) and in vitro gastrointestinal conditions on the isoflavone profile of soybean sprouts. The total isoflavones (4.07 mg/g) and the malonyl genistin (1.37 mg/g) had the highest contents on day 5 in the gastric phase. The highest isoflavone bioaccessibility was observed in daidzein, genistein, and glycitin. An increase in antioxidant capacity was found during germination (day 7 > day 5 > day 3); however, the same trend was not observed during in vitro digestion. In summary, the results indicate that soybean sprouts germinated for 5 days may be more beneficial for consumption since they have the highest and most readily absorbed levels of isoflavones. These data suggest that soybean sprouts may be a functional food that provides bioavailable antioxidants.

Asunto(s)

Antioxidantes , Digestión , Tracto Gastrointestinal , Germinación , Glycine max , Isoflavonas , Isoflavonas/metabolismo , Isoflavonas/análisis , Isoflavonas/química , Glycine max/metabolismo , Glycine max/química , Glycine max/crecimiento & desarrollo , Antioxidantes/metabolismo , Antioxidantes/química , Antioxidantes/análisis , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/crecimiento & desarrollo , Humanos , Modelos Biológicos , Disponibilidad Biológica , Semillas/química , Semillas/metabolismo , Semillas/crecimiento & desarrollo , Factores de Tiempo

RESUMEN

ETHNO-PHARMACOLOGICAL RELEVANCE: Huangqi Gegen decoction (HGD), which comprises Astragali Radix (AR) and Puerariae Radix (PR), is widely used to treat thrombosis in China. However, the mechanism underlying its synergistic effect in thrombosis treatment remains unclear. AIM OF THE STUDY: Following PR administration, low plasma exposure was reported for its primary ingredients. In this regard, this study examined the effect of AR on PR's antithrombotic efficacy with respect to the impact of Astragalus Polysaccharide (APS) on the oral delivery of Puerarin (PUE). MATERIALS AND METHODS: To evaluate the synergistic effect of HGD, a thrombus mice model was established via intraperitoneal injection of carrageenan. After treatment, histopathological observations were made, and the proportion of thrombus length in the tail, as well as the plasma APTT, PT, INR, and FIB levels, were detected. Molecular docking was employed to assess the PR ingredients that could inhibit the HMGB1/NF-κB/NLRP3 pathway. The Pharmacokinetics of PR ingredients in rats were also compared between the PR and HGD groups. Moreover, the effect of APS on the solubility, intestinal absorption, and pharmacokinetics of PUE was evaluated. Furthermore, the impact of APS on the antithrombotic efficacy of PUE was assessed. RESULTS: In mice, AR enhanced the antithrombotic effect of PR. This improved PR effect was associated with isoflavones-induced downregulation of the HMGB1/NF-κB/NLRP3 pathway. The synergistic effect resulting from the compatibility of HGD components was primarily achieved by improving the plasma exposure of PR isoflavones. Specifically, APS enhanced PUE's water solubility through the formation of self-assembly Nanoparticles, increasing its intestinal absorption and oral bioavailability, which, in turn, suppressed the HMGB1/NF-κB/NLRP3 pathway, thus improving its antithrombotic effect. CONCLUSIONS: Our findings revealed that APS improved PUE's plasma exposure, enhancing its inhibitory effect on the HMGB1/NF-κB/NLRP3 pathway. This mechanism presents a key aspect of the synergistic effect of HGD compatibility in thrombosis treatment.

Asunto(s)

Planta del Astrágalo , Sinergismo Farmacológico , Medicamentos Herbarios Chinos , Isoflavonas , Polisacáridos , Trombosis , Animales , Isoflavonas/farmacología , Isoflavonas/administración & dosificación , Isoflavonas/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Polisacáridos/farmacología , Polisacáridos/administración & dosificación , Masculino , Administración Oral , Trombosis/tratamiento farmacológico , Ratones , Planta del Astrágalo/química , Fibrinolíticos/farmacología , Fibrinolíticos/administración & dosificación , Pueraria/química , Modelos Animales de Enfermedad , Simulación del Acoplamiento Molecular , Astragalus propinquus/química , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo

RESUMEN

Osage orange trees (Maclura pomifera (Raf.) C.K.Schneid.) are distributed worldwide, particularly in south-east states of the USA. They produce large quantities of strong yellow fruits, bigger than oranges, but these fruits are inedible, with an acid milky juice which is little consumed by birds and insects. Extracts prepared from Osage orange fruits (hedge apple) have revealed a range of pharmacological properties of interest in human and veterinary medicine. In addition, Osage orange extracts can be used in agriculture and aquaculture, and as dyeing agent for the textile industry. Extracts contain potent antioxidant compounds, notably the isoflavonoids pomiferin and auriculasin, together with other terpenoids and flavonoids. The structural characteristics and pharmacological properties of the major prenylated isoflavones isolated from M. pomifera are discussed here, with a focus on the two phenolic compounds osajin and warangalone, and the two catechol analogues pomiferin and auriculasin. The mechanisms at the origin of their potent antioxidant and anti-inflammatory effects are presented, notably inhibition of xanthine oxidase, phosphodiesterase 5A and kinases such as RKS2 and kRAS. Osajin and auriculasin display marked anticancer properties, owing to their ability to inhibit tumor cell proliferation, migration and tumor angiogenesis. Different molecular mechanisms are discussed, including osajin­copper complexation and binding to quadruplex DNA. An overview of the mechanism of action of the prenylated isoflavones from Osage orange is presented, with the objective to promote their knowledge and to raise opportunities to better exploit the fruits of Osage orange, abundant but largely neglected at present.

Asunto(s)

Antioxidantes , Frutas , Isoflavonas , Maclura , Frutas/química , Isoflavonas/farmacología , Isoflavonas/aislamiento & purificación , Isoflavonas/química , Maclura/química , Humanos , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Estructura Molecular , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Prenilación , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Animales , Fenoles/farmacología , Fenoles/aislamiento & purificación , Benzopiranos

RESUMEN

Measuring the chemical composition in soybeans is time-consuming and laborious, and even simple near-infrared sensors generally require the creation of calibration curves before application. In this study, a new screening method for soybeans without calibration curves was investigated by combining the excitation emission matrix (EEM) and dimensionality reduction analysis. The EEMs of 34 soybean samples were measured, and representative chemical contents including crude protein, crude oil and isoflavone contents were measured by chemical analysis. Two methods of dimensionality reduction: principal component analysis (PCA) and t-distributed Stochastic Neighbor Embedding (t-SNE) were applied on the EEM data to obtain two-dimensional plots, which were divided into two regions with large or small amount of each chemical components. To classify the large or small levels of each of the chemical composition, machine learning classification models were constructed on the two-dimensional plots after dimensionality reduction. As a result, the classification accuracy was higher in t-SNE than in the combinations of PC1 and PC2 from PCA. Furthermore, in t-SNE, the classification accuracy reached over 90% for all the chemical components. From these results, t-SNE dimensionality reduction on the soybean EEM has the potential for easy and accurate screening of soybeans especially based on isoflavone contents.

Asunto(s)

Glycine max , Análisis de Componente Principal , Glycine max/química , Glycine max/clasificación , Isoflavonas/análisis , Isoflavonas/química , Aprendizaje Automático , Proteínas de Soja/análisis , Proteínas de Soja/clasificación , Proteínas de Soja/química

RESUMEN

Naturally occurring homoisoflavonoids isolated from some Liliaceae plants have been reported to have diverse biological activities (e.g., antioxidant, anti-inflammatory, and anti-angiogenic effects). The exact mechanism by which homoisoflavonones exert anti-neuroinflammatory effects against activated microglia-induced inflammatory cascades has not been well studied. Here, we aimed to explore the mechanism of homoisoflavonoid SH66 having a potential anti-inflammatory effect in lipopolysaccharide (LPS)-primed BV2 murine microglial cells. Microglia cells were pre-treated with SH66 followed by LPS (100 ng/mL) activation. SH66 treatment attenuated the production of inflammatory mediators, including nitric oxide and proinflammatory cytokines, by down-regulating mitogen-activated protein kinase signaling in LPS-activated microglia. The SH66-mediated inhibition of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex and the respective inflammatory biomarker-like active interleukin (IL)-1ß were noted to be one of the key pathways of the anti-inflammatory effect. In addition, SH66 increased the neurite length in the N2a neuronal cell and the level of nerve growth factor in the C6 astrocyte cell. Our results demonstrated the anti-neuroinflammatory effect of SH66 against LPS-activated microglia-mediated inflammatory events by down-regulating the NLRP3 inflammasome complex, with respect to its neuroprotective effect. SH66 could be an interesting candidate for further research and development regarding prophylactics and therapeutics for inflammation-mediated neurological complications.

Asunto(s)

Antiinflamatorios , Lipopolisacáridos , Microglía , Microglía/efectos de los fármacos , Microglía/metabolismo , Lipopolisacáridos/farmacología , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Línea Celular , Isoflavonas/farmacología , Isoflavonas/química , Citocinas/metabolismo , Óxido Nítrico/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo

RESUMEN

Seven new formononetin derivatives (1-7) were designed and prepared from formononetin (phase II phytoestrogen). The derivatives 9-butyl-3-(4-methoxyphenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (2) and 9-(furan-3-ylmethyl)-3-(4-methoxyphenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (7) promoted significant osteoblast formation by modulating the BMP/Smad pathway. Compound 7 exhibited potent antiosteoclastogenesis activity in RANKL-induced RAW264.7 cells and ovariectomy (OVX)-induced osteoporosis in mice by regulation of the RANK/RANKL/OPG pathway. Compound 7 regulated osteoblast and osteoclast simultaneously and showed better effect than the well-known drug ipriflavone in vivo, suggesting 7 as a patented antiosteoporosis candidate.

Asunto(s)

Isoflavonas , Osteoblastos , Osteoclastos , Osteoporosis , Ligando RANK , Isoflavonas/farmacología , Isoflavonas/química , Animales , Osteoblastos/efectos de los fármacos , Ratones , Osteoporosis/tratamiento farmacológico , Osteoclastos/efectos de los fármacos , Células RAW 264.7 , Ligando RANK/metabolismo , Ligando RANK/efectos de los fármacos , Femenino , Estructura Molecular , Ovariectomía , Osteoprotegerina

RESUMEN

The phytochemical investigation of extracts from Dalea nana roots and aerial parts led to the isolation of thirteen phenolic compounds. Three previously undescribed isoflavans, named verdeans A-C (1, 3, and 7), were characterized. Two additional isoflavans (2 and 5) were previously undescribed enantiomers of known compounds. A previously undescribed isoflavone (verdean D, 10) was found, and the known specialized metabolites, isoflavans 4, 6, 8, and 9, isoflavone 11, flavone 12, and a 2-arylbenzofuran 13, were also isolated. All but one (7) of the isoflavans were prenylated. The structures of the previously undescribed compounds were deduced by NMR spectroscopy, supported by HRESI mass spectrometry. The absolute configurations of 1-3, 5, and 7-9 were determined by ECD. Compounds 1, 3, 4, 6, and 8 exhibited in vitro antimicrobial activities, causing complete growth inhibition (MIC) at concentrations between 6.7 and 37.0 µM against Cryptococcus neoformans and between 8.9 and 25.0 µM against methicillin resistant Staphylococcus aureus (MRSA). The most broadly active previously undescribed compound was verdean A (1), with MIC values of 6.7 and 12.9 µM toward C. neoformans and MRSA, respectively, and an MIC of 10.0 µM against the often-intractable C. albicans.

Asunto(s)

Cryptococcus neoformans , Isoflavonas , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Isoflavonas/química , Isoflavonas/farmacología , Isoflavonas/aislamiento & purificación , Estructura Molecular , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Raíces de Plantas/química , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Antiinfecciosos/farmacología , Antiinfecciosos/química , Antiinfecciosos/aislamiento & purificación

RESUMEN

Enzymatic fructosylation has emerged as a strategy to enhance the hydrophilicity of polyphenols by introducing sugar moieties, leading to the development of phenolic glycosides, which exhibit improved solubility, stability, and biological activities compared to their non-glycosylated forms. This study provides a detailed analysis of the interactions between five phenolic fructosides (4MFPh, MFF, DFPh, MFPh, and MFPu) and twelve proteins (11ß-HS1, CRP, DPPIV, IRS, PPAR-γ, GK, AMPK, IR, GFAT, IL-1ß, IL-6, and TNF-α) associated with the pathogenesis of T2DM. The strongest interactions were observed for phlorizin fructosides (DFPh) with IR (-16.8 kcal/mol) and GFAT (-16.9 kcal/mol). MFPh with 11ß-HS1 (-13.99 kcal/mol) and GFAT (-12.55 kcal/mol). 4MFPh with GFAT (-11.79 kcal/mol) and IR (-12.11 kcal/mol). MFF with AMPK (-9.10 kcal/mol) and PPAR- γ (-9.71 kcal/mol), followed by puerarin and ferulic acid monofructosides. The fructoside group showed lower free energy binding values than the controls, metformin and sitagliptin. Hydrogen bonding (HB) was identified as the primary interaction mechanism, with specific polar amino acids such as serin, glutamine, glutamic acid, threonine, aspartic acid, and lysine identified as key contributors. ADMET results indicated favorable absorption and distribution characteristics of the fructosides. These findings provide valuable information for further exploration of phenolic fructosides as potential therapeutic agents for T2DM.

Asunto(s)

Hipoglucemiantes , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Fenoles/química , Fenoles/farmacología , Humanos , Simulación del Acoplamiento Molecular , Isoflavonas/química , Isoflavonas/metabolismo , Isoflavonas/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Florizina/química , Florizina/farmacología , Fructosa/química , Fructosa/metabolismo , Glicosilación , Ácidos Cumáricos/química , Ácidos Cumáricos/metabolismo

RESUMEN

Chemical proteomics using biotin probes of natural products have significantly advanced our understanding of molecular targets and therapeutic potential. This review highlights recent progress in the application of biotin probes of homoisoflavonoids for identifying binding proteins and elucidating mechanisms of action. Notably, homoisoflavonoids exhibit antiangiogenic, anti-inflammatory, and antidiabetic effects. A combination of biotin probes, pull-down assays, mass spectrometry, and molecular modeling has revealed how natural products and their derivatives interact with several proteins such as ferrochelatase (FECH), soluble epoxide hydrolase (sEH), inosine monophosphate dehydrogenase 2 (IMPDH2), phosphodiesterase 4 (PDE4), and deoxyhypusine hydroxylase (DOHH). These target identification approaches pave the way for new therapeutic avenues, especially in the fields of oncology and ophthalmology. Future research aimed at expanding the repertoire of target identification using biotin probes of homoisoflavonoids promises to further elucidate the complex mechanisms and develop new drug candidates.

Asunto(s)

Inhibidores de la Angiogénesis , Antiinflamatorios , Biotina , Humanos , Biotina/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/química , Animales , Isoflavonas/farmacología , Isoflavonas/química , Sondas Moleculares/química

RESUMEN

Nineteen flavonoids were isolated from the fruits of Psoralea corylifolia L., including a novel flavanol (3) and three novel isoflavones (12-14). Their chemical structures were unequivocally determined through comprehensive spectral data analysis. The anti-proliferative effect of the isolated flavonoids was assessed in vitro using the MTT assay. Molecular docking and ELISA were employed to determine the inhibitory effects of the active compounds on ALK5. Isobavachalcone was found to inhibit TGF-ß1 induced EMT in A549 cells by Wound healing assay and Transwell chamber assay. Immunofluorescence assay and Western blot assay showed that IBC could inhibit cytoskeleton rearrangement, reduce the phosphorylation of ALK5, ERK, and Smad, down-regulate Snail expression, and up-regulate E-cadherin expression in TGF-ß1 induced A549 cells, thereby exerting the potential inhibitory effects on epithelial-mesenchymal transition (EMT) process in A549 cells. The findings presented herein establish a fundamental basis for investigating the anti-proliferative and anti-metastatic properties of psoralen flavonoids in human non-small cell lung cancer.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Transición Epitelial-Mesenquimal , Flavonoides , Frutas , Neoplasias Pulmonares , Simulación del Acoplamiento Molecular , Psoralea , Humanos , Células A549 , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/química , Flavonoides/aislamiento & purificación , Frutas/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Estructura Molecular , Psoralea/química , Receptor Tipo I de Factor de Crecimiento Transformador beta , Relación Estructura-Actividad , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Isoflavonas/química , Isoflavonas/aislamiento & purificación , Isoflavonas/farmacología

RESUMEN

The non-covalent and covalent complexes of ultrasound treated soybean protein isolate (SPI) and soybean isoflavone (SI) were prepared, and the structure, physicochemical properties and in vitro digestion characteristics of SPI-SI complexes were investigated. Ultrasonic treatment increased the non-covalent and covalent binding degree of SPI with SI, and the 240 W ultrasonic covalent complexes had higher binding efficiency. Appropriate ultrasonic treatment caused more uniform particle size distribution, lower average particle size and higher surface charge, which enhanced the free sulfhydryl groups and surface hydrophobicity, thus improving the stability, solubility and emulsifying properties of complexes. Ultrasonic treatment resulted in more disordered secondary structure, tighter tertiary conformation, higher thermal stability and stronger SPI-SI covalent interactions of complexes. These structural modifications of particles had important effects on the chemical stability and gastrointestinal digestion fate of SI. The ultrasonic covalent complexation had a greater resistance to heat-induced chemical degradation of SI and improved its chemical stability. Furthermore, the 240 W ultrasonic covalent complexes showed lower protein digestibility during digestion, and provided stronger protection for SI, which improved the digestion stability and antioxidant activity. Therefore, appropriate ultrasound promoted SPI-SI interactions to improve the stability and functional properties of complexes, which provided a theoretical basis for the development of new complexes and their applications in functional foods.

Asunto(s)

Digestión , Interacciones Hidrofóbicas e Hidrofílicas , Isoflavonas , Tamaño de la Partícula , Solubilidad , Proteínas de Soja , Proteínas de Soja/química , Isoflavonas/química , Glycine max/química , Antioxidantes/química , Manipulación de Alimentos/métodos , Calor

RESUMEN

Pueraria lobata (P. lobata), a traditional anti-diabetic medicine mainly composed of flavonoids and isoflavones, has a long history in diabetes treatment in China. However, the anti-diabetic active component is still unclear. Recently, protein tyrosine phosphatase 1B (PTP1B) has been a hot therapeutic target by negatively regulating insulin signaling pathways. In this study, the spectrum-effect relationship analysis method was first used to identify the active components of P. lobata that inhibit PTP1B. The fingerprints of 12 batches of samples were established using high-performance liquid chromatography (HPLC), and sixty common peaks were identified. Meanwhile, twelve components were identified by a comparison with the standards. The inhibition of PTP1B activity was studied in vitro by using the p-nitrophenol method, and the partial least squares discriminant analysis, grey relational analysis, bivariate correlation analysis, and cluster analysis were used to analyze the bioactive compounds in P. lobata. Peaks 6, 9 (glycitin), 11 (genistin), 12 (4'-methoxypuerarin), 25, 34, 35, 36, 53, and 59 were considered as potentially active substances that inhibit PTP1B. The in vitro PTP1B inhibitory activity was confirmed by glycitin, genistin, and 4'-methoxypuerarin. The IC50s of the three compounds were 10.56 ± 0.42 µg/mL, 16.46 ± 0.29 µg/mL, and 9.336 ± 0.56 µg/mL, respectively, indicating the obvious PTP1B inhibitory activity. In brief, we established an effective method to identify PTP1B enzyme inhibitors in P. lobata, which is helpful in clarifying the material basis of P. lobata on diabetes. Additionally, it is evident that the spectrum-effect relationship method serves as an efficient approach for identifying active compounds, and this study can also serve as a reference for screening bioactive constituents in traditional Chinese medicine.

Asunto(s)

Inhibidores Enzimáticos , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Pueraria , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Pueraria/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Cromatografía Líquida de Alta Presión , Isoflavonas/farmacología , Isoflavonas/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Humanos