RESUMEN
The encapsulation of the 3-deoxyanthocyanidins (3-DXA) red dye, extracted from sorghum (Sorghum bicolor L.) leaves, was explored for food application. The extracts showed antioxidant activity at concentrations ranging from 803 to 1210 µg mL-1 and did not reveal anti-inflammatory or cytotoxic properties, indicating their potential for food application. Encapsulation was performed with two carrier agents (maltodextrin and Arabic gum) in different proportions (1:1, 2:1 and 1.5:2.5 (w/w)). The microparticles produced by freeze-drying and spray-drying were studied according to the concentration of the dye, the encapsulation efficiency, the process yield, the solubility and the colour of the powders. The dye extracts are released from the microparticles at different pHs. The variation in ratio composition of the 3-DXA encapsulation was assessed by principal component analysis (PCA) using data from ten physicochemical parameters. The results indicated that the maltodextrin at the 2:1 ratio had a higher dye concentration and total phenolic content (TPC) at pH 6. This ratio was selected to produce the microparticles by freeze-drying and spray-drying, and the particles were used in the temperature stability tests at pH 6. The results suggest that the freeze-drying process offers better protection to 3-DXA, with a degradation percentage of 22% during the heating period (80 °C for 18 h), compared to the non-encapsulated dye (48%). However, there were no significant differences between the two polymeric agents. The non-encapsulated 3-DXA was evaluated as control and lost 48% of the total colour with the same treatment. Red dyes from sorghum leaf by-products may constitute promising ingredients for the food industry and increase the value of this crop.
RESUMEN
The looming urgency of feeding the growing world population along with the increasing consumers' awareness and expectations have driven the evolution of food production systems and the processes and products applied in the food industry. Although substantial progress has been made on food additives, the controversy in which some of them are still shrouded has encouraged research on safer and healthier next generations. These additives can come from natural sources and confer numerous benefits for health, beyond serving the purpose of coloring or preserving, among others. As limiting factors, these additives are often related to stability, sustainability, and cost-effectiveness issues, which justify the need for innovative solutions. In this context, and with the advances witnessed in computers and computational methodologies for in silico experimental aid, the development of new safer and more efficient natural additives with dual functionality (colorant and preservative), for instance by the copigmentation phenomena, may be achieved more efficiently, circumventing the current difficulties.
Asunto(s)
Colorantes de Alimentos , Aditivos Alimentarios , Industria de Alimentos , Conservantes de Alimentos , Industria de Procesamiento de AlimentosRESUMEN
Water extracts from sea lavender (Limonium algarvense Erben) plants cultivated in greenhouse conditions and irrigated with freshwater and saline aquaculture effluents were evaluated for metabolomics by liquid chromatography-tandem high-resolution mass spectrometry (LC-HRMS/MS), and functional properties by in vitro and ex vivo methods. In vitro antioxidant methods included radical scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric-reducing antioxidant power (FRAP), and copper and iron chelating assets. Flowers' extracts had the highest compounds' diversity (flavonoids and its derivatives) and strongest in vitro antioxidant activity. These extracts were further tested for ex vivo antioxidant properties by oxidative haemolysis inhibition (OxHLIA), lipid peroxidation inhibition by thiobarbituric acid reactive substances (TBARS) formation, and anti-melanogenic, anti-tyrosinase, anti-inflammation, and cytotoxicity. Extract from plants irrigated with 300 mM NaCl was the most active towards TBARS (IC50 = 81 µg/mL) and tyrosinase (IC50 = 873 µg/mL). In OxHLIA, the activity was similar for fresh- and saltwater-irrigated plants (300 mM NaCl; IC50 = 136 and 140 µg/mL, respectively). Samples had no anti-inflammatory and anti-melanogenic abilities and were not toxic. Our results suggest that sea lavender cultivated under saline conditions could provide a flavonoid-rich water extract with antioxidant and anti-tyrosinase properties with potential use as a food preservative or as a functional ingredient in herbal supplements.
RESUMEN
The objective of this work was to determine the potential bioactive properties of extracts from bio-residues of pinhão (Araucaria angustifolia (Bertol.) Kuntze) seeds, namely the α-amylase and cholinesterase inhibition, cytotoxicity, and anti-inflammatory properties. The pinhão extracts evaluated were obtained from cooking water (CW) and as an ethanolic extract from residual pinhão seed shells (PS). Catechin was the major compound found in both extracts. The PS extract presented higher antioxidant levels and the better inhibition of human salivary and porcine pancreatic α-amylases when compared to the CW extract. Also, based on in vivo evaluations, the PS extract did not differ significantly from acarbose when compared to a control group. The most potent inhibitor of cholinesterases was the CW extract. No cytotoxicity toward normal cells was detected, and neither extract showed anti-inflammatory activity. The PS extract presented cytotoxic activity toward non-small-cell lung, cervical, hepatocellular and breast carcinoma cell lines. Overall, the results demonstrated the potential bioactivity of extracts obtained from pinhão bio-residues.
Asunto(s)
Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Araucaria/química , Inhibidores de la Colinesterasa/farmacología , Extractos Vegetales/farmacología , alfa-Amilasas/antagonistas & inhibidores , Animales , Antioxidantes/farmacología , Catequina/análisis , Línea Celular Tumoral , Colinesterasas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Extractos Vegetales/análisis , Semillas/química , alfa-Amilasas/metabolismoRESUMEN
Juglans regia L. (walnut) green husks are an important fraction of waste resulting from the walnut production, thus representing an interesting natural matrix to explore as a source of bioactive compounds. In this work, the hydroethanolic extract of walnut green husks was studied considering the phytochemical composition and the biological activity using different cell model assays, most of them evaluated for the first time for this matrix. From the HPLC-DAD-ESI/MSn analysis, sixteen compounds were identified, being the extract mostly composed of naphthalene derivatives (including tetralone derivatives) and less abundant in phenolic compounds (hydroxycinnamic acids and flavonols). The cytotoxic potential of the extract was assessed against tumour (MCF-7, NCI-H460, HeLa and HepG2) and non-tumour (PLP2) cell lines. Moreover, the antioxidant activity of the extract was evaluated by inhibition of the oxidative haemolysis (OxHLIA) and the formation of thiobarbituric acid reactive substances (TBARS), and the anti-inflammatory potential by the inhibition of the NO production by the RAW264.7 cell culture. The antibacterial effects of the extract were also evaluated against Gram-negative and Gram-positive bacteria. The results obtained represent a stepping stone for the development of future applications using walnut green husks as a source of added value compounds with bioactive potential.
Asunto(s)
Antibacterianos/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Juglans/química , Nueces/química , Fitoquímicos/farmacología , Animales , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Bacterias/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/química , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Fenoles/química , Fenoles/aislamiento & purificación , Fenoles/farmacología , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Porcinos , Tetralonas/química , Tetralonas/aislamiento & purificación , Tetralonas/farmacologíaRESUMEN
Jabuticaba (Myrciaria jaboticaba (Vell.) Berg) is a Brazilian berry, very appreciated for in natura consumption. However, its epicarp is not normally consumed due to its stiffness and astringent taste, and in manufacture of products from jabuticaba fruit, it is responsible for the generation of large amounts of residues. The exploration of by-products is becoming important for the obtainment of valuable bioactive compounds for food and pharmaceutical industries. In this context, jabuticaba epicarp was studied regarding its chemical composition, namely in terms of phenolic compounds, tocopherols, and organic acids, and its bioactive properties, such as antioxidant, anti-proliferate, anti-inflammatory, and antimicrobial activities. A total of sixteen phenolic compounds, four tocopherols and six organic acids were identified in jabuticaba epicarp. Regarding bioactive properties, it showed high antioxidant activity, also presenting moderate anti-inflammatory, anti-proliferative, and antimicrobial activities. The extract did not present hepatotoxicity, confirming the possibility of its applications without toxicity issues.
Asunto(s)
Myrtaceae/química , Extractos Vegetales/química , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Bacterias/efectos de los fármacos , Brasil , Frutas/química , Frutas/metabolismo , Taninos Hidrolizables/química , Taninos Hidrolizables/aislamiento & purificación , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Myrtaceae/metabolismo , Óxido Nítrico/metabolismo , Fenoles/química , Fenoles/aislamiento & purificación , Células RAW 264.7 , Tocoferoles/química , Tocoferoles/aislamiento & purificaciónRESUMEN
This study aims to give an unprecedented contribution on the chemical composition and bioactivities of the most produced and appreciated Portuguese fig variety ("Pingo de Mel") with the view of expanding the knowledge on its potentialities. An advanced characterization of its peel and pulp parts was carried out. Four free sugars (glucose, fructose, trehalose and sucrose), 5 organic acids (oxalic, quinic, malic, citric, and succinic acids), tocopherols in all their 4 forms, besides 23 fatty acids were detected in the samples. Fifteen different phenolic components were found in the peel hydroethanolic extract; whereas 12 were detected in the pulp hydroethanolic extract. Quercetin-3-O-rutinoside (rutin) was the major constituent of the peel, accounting for 33.8% of its phenolic content, followed by 5-O-caffeoylquinic acid and vanillic acid malonyl di-deoxyhexoside. Caffeic acid derivatives, such as caffeic acid hexosides, were the major components of pulp, followed by vanillic acid derivatives and O-caffeoylquinic acid. Both extracts displayed promising antioxidant capacities in all methods used, namely the 2,2-diphenyl-1-picrylhydrazyl radical-scavenging, the reducing power, the inhibition of ß-carotene bleaching assays, the thiobarbituric acid reactive substances assay and the oxidative haemolysis inhibition assay; however, the peel presented significantly lower IC50 values than pulp. The extracts showed practically identical antibacterial capacities, being effective against methicillin-sensitive Staphylococcus aureus (MICsâ¯=â¯2.5â¯mg/mL), besides methicillin-resistant S. aureus, Escherichia coli and Morganella morganii (MICsâ¯=â¯5â¯mg/mL). The obtained results evidence that the fig peel is superior to the corresponding pulp as it relates to nutritional and phenolic profiles as well as bioactivities, endorsing the urgency in valorising and exploiting this usually discarded industrial by-product.
Asunto(s)
Ficus/química , Valor Nutritivo , Fitoquímicos/análisis , Antibacterianos/análisis , Antioxidantes/análisis , Ácidos Cafeicos/análisis , Ácido Clorogénico/análogos & derivados , Ácido Clorogénico/análisis , Cromatografía Líquida de Alta Presión , Análisis de los Alimentos , Frutas/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Polifenoles/análisis , Portugal , Ácido Quínico/análogos & derivados , Ácido Quínico/análisis , Rutina/análisis , Tocoferoles/análisisRESUMEN
Pereskia aculeata Miller, known worldwide as ora-pro-nobis, is a highly nutritive species of the Cactaceae family from the Brazilian Atlantic Forest. In this work, we report inedited information on the phenolic profile of P. aculeata leaves, besides a broad study of their antioxidant potential using a set of five different methods. A total of ten phenolic compounds were identified, such as two phenolic acids (caffeic acid derivatives) and eight flavonoids (quercetin, kaempferol and isorhamnetin glycoside derivatives). Caftaric acid was the extract's major phenolic constituent, accounting for more than 49% of the phenolic content, followed by quercetin-3-O-rutinoside (14.99%) and isorhamnetin-O-pentoside-O-rutinoside (9.56%). Overall, the ora-pro-nobis leaf extract showed relevant values of antioxidant capacity, with higher activities than the Trolox in the DPPH and ABTS trials. The antimicrobial activity exhibited by the extract against both Gram-positive and Gram-negative bacteria suggests the presence of a broad spectrum of phytochemicals with antibiotic activity.
Asunto(s)
Cactaceae/química , Fitoquímicos/química , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antioxidantes/química , Brasil , Cactaceae/metabolismo , Células Cultivadas , Flavonoides/química , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Bosques , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Fenoles/química , Fenoles/aislamiento & purificación , Fenoles/farmacología , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Extractos Vegetales/química , Hojas de la Planta/química , Hojas de la Planta/metabolismoRESUMEN
The inflorescences of Calluna vulgaris were nutritionally and chemically characterized. Furthermore, different organic and aqueous extracts were prepared for the evaluation of their bioactive properties. From the obtained results, carbohydrates were the major compounds, followed by protein, lipid and ashes. It was possible to identify the sugars fructose and glucose, five organic acids, 26 individual fatty acids and the four tocopherol isoforms. Concerning the extract composition, 12 phenolic compounds were identified, with myricetin-3-O-glucoside and myricetin-O-rhamnoside predominating. Concerning the bioactive effects, the more polar extracts showed not only the highest amount in phenolic compounds, but also the strongest antioxidant and antibacterial activities. In contrast, for the anti-inflammatory and cytotoxic potential, the most effective extracts were the n-hexane and the ethyl acetate extracts, respectively. C. vulgaris presented a wide range of biological effects, highlighting their capacity to inhibit pathogenic bacteria without affecting beneficial microflora, corroborating their use in traditional medicine.
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Bacterias/efectos de los fármacos , Calluna/química , Microbiota/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Vagina/microbiología , Antibacterianos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Ácidos Grasos/química , Ácidos Grasos/farmacología , Femenino , Humanos , Pruebas de Sensibilidad Microbiana , Fenoles/química , Fenoles/farmacología , Tocoferoles/química , Tocoferoles/farmacologíaRESUMEN
A series of enantiopure isoxazolidines (3a-c) were synthesized by 1,3-dipolar cycloaddition between a (-)-menthone-derived nitrone and various terminal alkenes. The screened compounds were evaluated for their antioxidant activity by two in vitro antioxidant assays, including ß-carotene/linoleic acid bleaching, and inhibition of lipid peroxidation (thiobarbituric acid reactive species, TBARS). The results revealed that compound 3b (EC50 = 0.55 ± 0.09 mM) was the most potent antioxidant as compared to the standard drug (EC50 = 2.73 ± 0.07 mM) using the TBARS assay. Furthermore, the antimicrobial activity was assessed using disc diffusion and microdilution methods. Among the synthesized compounds, 3c was found to be the most potent antimicrobial agent as compared to the standard drug. Subsequently, the acute toxicity study has also been carried out for the newly synthesized compounds and the experimental studies revealed that all compounds were safe up to 500 mg/kg and no death of animals were recorded. The cytotoxicity of these compounds was assessed by the MTT cell proliferation assay against the continuous human cell lines HeLa and compound 3c (GI50 = 46.2 ± 1.2 µM) appeared to be more active than compound 3a (GI50 = 200 ± 2.8 µM) and 3b (GI50 = 1400 ± 7.8 µM). Interestingly, all tested compounds displayed a good α-amylase inhibitory activity in competitive manner with IC50 values ranging between 23.7 and 64.35 µM when compared to the standard drug acarbose (IC50 = 282.12 µM). In addition, molecular docking studies were performed to understand the possible binding and the interaction of the most active compounds to the α-amylase pocket.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Simulación por Computador , Isoxazoles/química , Isoxazoles/farmacología , Antiinfecciosos/metabolismo , Antiinfecciosos/toxicidad , Antineoplásicos/metabolismo , Antineoplásicos/toxicidad , Células HeLa , Humanos , Isoxazoles/metabolismo , Isoxazoles/toxicidad , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Conformación Proteica , Estereoisomerismo , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/química , alfa-Amilasas/metabolismoRESUMEN
Pleurotus sajor-caju (PSC) is an edible mushroom used in food supplements, presenting antitumor properties through induction of cell death pathways. The PSC potential against colorectal cancer was analyzed by exposing HCT116wt cells to different PSC extracts. The PSC n-hexane extract (PSC-hex) showed the highest cytotoxicity effect (IC50 value 0.05â¯mg/mL). The observed cytotoxicity was then associated to apoptosis-promoting and cell cycle-arrest pathways. PSC-hex was able to induce apoptosis related to breakdown of mitochondrial membrane potential and ROS generation. The absence of cytotoxicity in HTC116-p53 and HTC116-Bax cells, alongside with an increase in p53, Bax and Caspase-3 expression, and decrease in Bcl-2 expression, supports that the pro-apoptotic effect is probably induced through a p53 associated pathway. PSC-hex induced cell cycle arrest at G2/M in HCT116wt without cytotoxicity in HTC116-p21â¯cells. These findings suggest that a p21/p53â¯cell cycle regulation pathway is probably disrupted by compounds present on PSC-hex. Identification of the major components was then performed with ergosta-5,7,22-trien-3ß-ol representing 30.6% of total weight. In silico docking studies of ergosta-5,7,22-trien-3ß against Bcl-2 were performed and results show a credible interaction with the Bcl-2 hydrophobic cleft. The results show that PSC-hex can be used as supplementary food for adjuvant therapy in colorectal carcinoma.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/terapia , Suplementos Dietéticos , Pleurotus/química , Antineoplásicos/aislamiento & purificación , Caspasa 3/metabolismo , División Celular/efectos de los fármacos , Línea Celular , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Ergosterol/análogos & derivados , Ergosterol/aislamiento & purificación , Ergosterol/farmacología , Fase G2/efectos de los fármacos , Células HCT116 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Angiogenesis is the natural and physiologic process of growing blood vessels from pre-existing ones. Pathological angiogenesis occurs when the precise balance of all the molecular pathways that regulate angiogenesis is disrupted, and this process is a critical step in many diseases, including cancer. A limited number of antiangiogenic synthetic drugs have been developed. However, due to toxicity and side effects issues, the search for alternative to existing drugs is ongoing. In this sense, natural molecules obtained from plants or macrofungi, have demonstrated extraordinary potential in the treatment of angiogenesis-related pathologies, specially taking into consideration its absence or very low toxicity, when compared to synthetic drugs. Using natural compounds as potential angiogenesis modulators is thus a promising field of research, supporting the creation of novel therapies able to reduce the use of drugs and associated side effects. In this review, the current status of antiangiogenic drugs and the wide variety of natural extracts and molecules with antiangiogenic capacities, as well as the angiogenesis molecular pathways and therapeutic targets, are presented. Finally, the challenges that need to be overcome in order to increase the use of natural compounds for clinical purposes are discussed.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Productos Biológicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Inhibidores de la Angiogénesis/química , Productos Biológicos/química , Hongos/química , Humanos , Estructura Molecular , Neoplasias/irrigación sanguínea , Plantas Medicinales/químicaRESUMEN
A study with Pleurotus sajor-caju was conducted to: evaluate the nutritional and chemical composition of the fruiting bodies; optimize the preparation of bioactive phenolic extracts; and characterize the optimized extract in terms of bioactive compounds and properties. P. sajor-caju revealed an equilibrated nutritional composition with the presence of hydrophilic (sugars and organic acids) and lipophilic (tocopherols and PUFA) compounds. p-Hydroxybenzoic, p-coumaric and cinnamic acids were identified in the extract obtained with ethanol (30g/l ratio) at 55°C for 85min. This extract showed antioxidant properties (mainly reducing power and lipid peroxidation inhibition), antibacterial activity against MRSA and MSSA and cytotoxicity against NCI-H460, MCF-7 and HeLa. Furthermore, as the extract showed capacity to inhibit NO production in Raw 264.7 macrophages, molecular docking studies were performed to provide insights into the anti-inflammatory mechanism of action, through COX-2 inhibition by the phenolic acids identified.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Valor Nutritivo , Pleurotus/química , Antiinflamatorios no Esteroideos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antioxidantes/química , Etanol/química , Células HeLa , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Tocoferoles/análisisRESUMEN
Angiogenesis is a process by which new blood vessels are formed from the pre-existing vasculature, and it is a key process that leads to tumour development. Some studies have recognized phenolic compounds as chemopreventive agents; flavonoids, in particular, seem to suppress the growth of tumor cells modifying the cell cycle. Herein, the antiangiogenic activity of Roman chamomile (Chamaemelum nobile L.) extracts (methanolic extract and infusion) and the main phenolic compounds present (apigenin, apigenin-7-O-glucoside, caffeic acid, chlorogenic acid, luteolin, and luteolin-7-O-glucoside) was evaluated through enzymatic assays using the tyrosine kinase intracellular domain of the Vascular Endothelium Growth Factor Receptor-2 (VEGFR-2), which is a transmembrane receptor expressed fundamentally in endothelial cells involved in angiogenesis, and molecular modelling studies. The methanolic extract showed a lower IC50 value (concentration that provided 50% of VEGFR-2 inhibition) than the infusion, 269 and 301 µg mL(-1), respectively. Regarding phenolic compounds, luteolin and apigenin showed the highest capacity to inhibit the phosphorylation of VEGFR-2, leading us to believe that these compounds are involved in the activity revealed by the methanolic extract.
Asunto(s)
Manzanilla/química , Extractos Vegetales/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Apigenina/farmacología , Flavonoides/farmacología , Humanos , Luteolina/farmacología , Metanol , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Neovascularización Patológica/prevención & control , Fenoles/farmacología , Fosforilación/efectos de los fármacos , Extractos Vegetales/químicaRESUMEN
The phytochemical profiles and bioactivities of red, white and pink globe amaranth (Gomphrena haageana K., Gomphrena globosa var. albiflora and Gomphrena sp., respectively), much less studied than the purple species (G. globosa L.), were compared. The chemical characterization of the samples included the analysis of macronutrients and individual profiles of sugars, organic acids, fatty acids, tocopherols, and phenolic compounds. Their bioactivity was evaluated by determining the antioxidant and anti-inflammatory activities; the absence of cytotoxicity was also determined. Red and pink samples showed the highest sugar content. Otherwise, the white sample gave the highest level of organic acids, and together with the pink one showed the highest tocopherol and PUFA levels. Quercetin-3-O-rutinoside was the major flavonol in white and pink samples, whereas a tetrahydroxy-methylenedioxyflavone was the major compound in the red variety, which revealed a different phenolic profile. The pink globe amaranth hydromethanolic extract revealed the highest antioxidant activity, followed by those of red and white samples. The anti-inflammatory activity was more relevant in red and pink varieties. None of the samples presented toxicity in liver cells. Overall, these samples can be used in bioactive formulations against inflammatory processes and in free radical production.
Asunto(s)
Amaranthus/química , Antiinflamatorios/química , Antioxidantes/química , Fitoquímicos/química , Extractos Vegetales/química , Amaranthus/clasificación , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Línea Celular , Color , Humanos , Hígado/efectos de los fármacos , Hígado/inmunología , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , PorcinosRESUMEN
The synthesis and biological evaluation of novel 1-aryl-3-[2-, 3- or 4-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 3, 4 and 5 as VEGFR-2 tyrosine kinase inhibitors, are reported. The 1-aryl-3-[3-(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas 4a-4h, with the arylurea in the meta position to the thioether, showed the lowest IC50 values in enzymatic assays (10-206 nM), the most potent compounds 4d-4h (IC50 10-28 nM) bearing hydrophobic groups (Me, F, CF3 and Cl) in the terminal phenyl ring. A convincing rationalization was achieved for the highest potent compounds 4 as type II VEGFR-2 inhibitors, based on the simultaneous presence of: (1) the thioether linker and (2) the arylurea moiety in the meta position. For compounds 4, significant inhibition of Human Umbilical Vein Endothelial Cells (HUVECs) proliferation (BrdU assay), migration (wound-healing assay) and tube formation were observed at low concentrations. These compounds have also shown to increase apoptosis using the TUNEL assay. Immunostaining for total and phosphorylated (active) VEGFR-2 was performed by Western blotting. The phosphorylation of the receptor was significantly inhibited at 1.0 and 2.5 µM for the most promising compounds. Altogether, these findings point to an antiangiogenic effect in HUVECs.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Urea/análogos & derivados , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Simulación del Acoplamiento Molecular , Neovascularización Fisiológica/efectos de los fármacos , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
In the present work, the knowledge on target proteins of standard antibiotics was extended to antimicrobial mushroom compounds. Docking studies were performed for 34 compounds in order to evaluate their affinity to bacterial proteins that are known targets for some antibiotics with different mechanism of action: inhibitors of cell wall synthesis, inhibitors of protein synthesis, inhibitors of nucleic acids synthesis and antimetabolites. After validation of the molecular docking approach, virtual screening of all the compounds was performed against penicillin binding protein 1a (PBP1a), alanine racemase (Alr), d-alanyl-d-alanine synthetase (Ddl), isoleucyl-tRNA sinthetase (IARS), DNA gyrase subunit B, topoisomerase IV (TopoIV), dihydropteroate synthetase (DHPS) and dihydrofolate reductase (DHFR) using AutoDock4. Overall, it seems that for the selected mushroom compounds (namely, enokipodins, ganomycins and austrocortiluteins) the main mechanism of the action is the inhibition of cell wall synthesis, being Alr and Ddl probable protein targets.
Asunto(s)
Antraquinonas/química , Hidroquinonas/química , Simulación del Acoplamiento Molecular , Sesquiterpenos/química , Agaricales/química , Antraquinonas/farmacología , Antibacterianos/química , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/biosíntesis , Dihidropteroato Sintasa/antagonistas & inhibidores , Humanos , Hidroquinonas/farmacología , Pruebas de Sensibilidad Microbiana , Sesquiterpenos/farmacologíaRESUMEN
New fluorinated and methoxylated di(hetero)arylethers and di(hetero)arylamines were prepared functionalizing the 7-position of the thieno[3,2-b]pyridine, using copper (C-O) or palladium (C-N) catalyzed couplings, respectively, of the 7-bromothieno[3,2-b]pyridine, also prepared, with ortho, meta and para fluoro or methoxy phenols and anilines. The compounds obtained were evaluated for their growth inhibitory activity on the human tumor cell lines MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), HCT15 (colon carcinoma), HepG2 (hepatocellular carcinoma) and HeLa (cervical carcinoma). The most active compounds, a di(hetero)arylether with a methoxy group in the meta position relative to the ether function and two di(hetero)arylamines with a methoxy group either in the ortho or in the meta position relative to the NH, were further tested at their GI50 concentrations on NCI-H460 cells causing pronounced alterations in the cell cycle profile and a strong and significant increase in the programmed death of these cells. The fluorinated and the other methoxylated compounds did not show important activity, presenting high GI50 values in all the cell lines tested. Furthermore, the hepatotoxicity of the compounds was assessed using porcine liver primary cells (PLP2), established by some of us. Results showed that one of the most active compounds was not toxic to the non-tumor cells at their GI50 concentrations showing to be the most promising as antitumoral.
Asunto(s)
Aminas/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Éteres/química , Neoplasias/patología , Piridinas/farmacología , Tiofenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
The vascular endothelial growth factor receptor-2 (VEGFR-2) is a tyrosine kinase receptor involved in the growth and differentiation of endothelial cells that are implicated in tumor-associated angiogenesis. In this study, novel 1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas were synthesized and evaluated for the VEGFR-2 tyrosine kinase inhibition. Three of these compounds showed good VEGFR-2 inhibition presenting low IC50 values (150-199 nM) in enzymatic assays, showing also a significant proliferation inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) at low concentrations (0.5-1 µM), using the Bromodeoxyuridine (BrdU) assay, not affecting cell viability. The determination of the total and phosphorylated (active) VEGFR-2 was performed by western blot, and it was possible to conclude that the compounds significantly inhibit the phosphorylation of the receptor at 1 µM pointing to their antiproliferative mechanism of action in HUVECs. The molecular rationale for inhibiting the tyrosine kinase domain of VEGFR-2 was also performed and discussed using molecular docking studies.
Asunto(s)
Neovascularización Patológica/genética , Compuestos de Fenilurea/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Sitios de Unión , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%-59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10-15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.