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1.
Food Chem ; 302: 125373, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31442706

RESUMO

The aim of this work was to investigate and compare the phenolic profile of 15 wild growing blackthorn (Prunus spinosa L.) genotypes from the slopes of Fruska Gora mountain in north Serbia. Their effect in inhibiting i) α-amylase and α-glucosidase activities and ii) colorectal cancer cell line (HT29) growth was also studied. Blackthorn fruit extracts exhibited high phenolic content being enrich in anthocyanins. Principal component analysis was used to correlate the bioactive response with phenolic composition. It was found that derivatives quercetin and anthocyanin peonidin are the major contributors of the inhibition of carbohydrates hydrolyzing enzymes as well as with the antiproliferative effect of blackthorn. Among all samples, the genotype from Beska locality showed the higher capacity in inhibiting alpha-amylase, alpha-glucosidase and HT29 cell growth. Because of high anthocyanin content and higher bioactive response, these genotypes could be recommended for the further cultivation and investigation.


Assuntos
Polifenóis/análise , Prunus/química , Prunus/genética , Antocianinas/análise , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/análise , Ácido Clorogênico/análogos & derivados , Ácido Clorogênico/análise , Cromatografia Líquida de Alta Pressão , Análise de Alimentos/estatística & dados numéricos , Frutas/química , Genótipo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Células HT29 , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Análise de Componente Principal , Quercetina/análise , Ácido Quínico/análogos & derivados , Ácido Quínico/análise , Sérvia , alfa-Amilases/antagonistas & inibidores
2.
Nutrients ; 11(2)2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30717428

RESUMO

Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% ± 5.27% compared to 63.55% ± 17.49% for 2D), upregulation of CD44, PROM1, SOX9, and SNAI1 genes (1.83 ± 0.34, 2.54 ± 0.51, 2.03 ± 0.15, and 6.12 ± 1.59 times) and high self-renewal capability (352 ± 55 colonies compared to 253 ± 42 for 2D). Incubation with OPE (1 mg/mL) significantly inhibited cell proliferation and modulated cancer stemness and self-renewal ability: colony formation, ALDH1 activity, and the expression of cancer stemness biomarkers PROM1 and LGR5 were significantly reduced (0.66 ± 0.15 and 0.51 ± 0.14 times, respectively). Among all PMFs, tangeretin was the most efficient in targeting the CSC population by decreasing colony formation and the expression of PROM1 and LGR5. Scutellarein tetramethylether was shown to modulate markers of mesenchymal/metastatic transition (increasing CDH1 and reducing ZEB1 and SNAI1) and nobiletin was capable of downregulating PROM1 and SNAI1 expression. Importantly, all PMFs and OPE were shown to synergistically interact with 5-fluorouracil, improving the antiproliferative response of this drug.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Citrus/química , Neoplasias Colorretais/tratamento farmacológico , Flavonas/uso terapêutico , Fluoruracila/uso terapêutico , Células-Tronco Neoplásicas/efeitos dos fármacos , Fitoterapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células , Células Cultivadas , Neoplasias Colorretais/metabolismo , Flavonas/farmacologia , Frutas , Células HT29 , Humanos , Proteínas de Neoplasias/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
3.
Nutr Cancer ; 70(2): 257-266, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29313727

RESUMO

Polymethoxylated flavones (PMFs) have been recognized to inhibit colorectal cancer proliferation through various mechanisms, however most of these studies have been performed on cells grown as monolayers that present limitations in mimicking the 3D tumor architecture and microenvironment. The main aim of this study was to investigate the anticancer potential of an orange peel extract (OPE) enriched in PMFs in a 3D cell model of colorectal cancer. The OPE was developed by supercritical fluid extraction and the anticancer effect was evaluated in HT29 spheroids cultures in a stirred-tank based system. Results showed that OPE inhibited cell proliferation, induced cell cycle arrest (G2/M phase), promoted apoptosis, and reduced ALDH+ population on HT29 spheroids. The antiproliferative activity was significantly lower than that obtained for 2D model (EC50 value of 0.43 ± 0.02 mg/mL) and this effect was dependent on diameter and cell composition/phenotype of spheroids derived from different culture days (day 3 - 0.53 ± 0.05 mg/mL; day 5 - 0.55 ± 0.03 mg/mL; day 7 - 1.24 ± 0.15 mg/mL). HT29 spheroids collected at day 7 presented typical characteristics of in vivo solid tumors including a necrotic/apoptotic core, hypoxia regions, presence of cancer stem cells, and a less differentiated invasive front. Nobiletin, sinesentin, and tangeretin were identified as the main compounds responsible for the anticancer activity.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Citrus sinensis/química , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Flavonas/farmacologia , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células/métodos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Flavonas/análise , Flavonas/química , Células HT29 , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia
4.
Nutrients ; 9(4)2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28394276

RESUMO

Colorectal cancer (CRC) recurrence is often attributable to circulating tumor cells and/or cancer stem cells (CSCs) that resist to conventional therapies and foster tumor progression. Isothiocyanates (ITCs) derived from Brassicaceae vegetables have demonstrated anticancer effects in CRC, however little is known about their effect in CSCs and tumor initiation properties. Here we examined the effect of ITCs-enriched Brassicaceae extracts derived from watercress and broccoli in cell proliferation, CSC phenotype and metastasis using a previously developed three-dimensional HT29 cell model with CSC-like traits. Both extracts were phytochemically characterized and their antiproliferative effect in HT29 monolayers was explored. Next, we performed cell proliferation assays and flow cytometry analysis in HT29 spheroids treated with watercress and broccoli extracts and respective main ITCs, phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). Soft agar assays and relative quantitative expression analysis of stemness markers and Wnt/ß-catenin signaling players were performed to evaluate the effect of these phytochemicals in stemness and metastasis. Our results showed that both Brassicaceae extracts and ITCs exert antiproliferative effects in HT29 spheroids, arresting cell cycle at G2/M, possibly due to ITC-induced DNA damage. Colony formation and expression of LGR5 and CD133 cancer stemness markers were significantly reduced. Only watercress extract and PEITC decreased ALDH1 activity in a dose-dependent manner, as well as ß-catenin expression. Our research provides new insights on CRC therapy using ITC-enriched Brassicaceae extracts, specially watercress extract, to target CSCs and circulating tumor cells by impairing cell proliferation, ALDH1-mediated chemo-resistance, anoikis evasion, self-renewal and metastatic potential.


Assuntos
Anticarcinógenos/metabolismo , Brassica/química , Neoplasias Colorretais/prevenção & controle , Isotiocianatos/metabolismo , Nasturtium/química , Metástase Neoplásica/prevenção & controle , Extratos Vegetais/metabolismo , Anticarcinógenos/análise , Anticarcinógenos/química , Anticarcinógenos/isolamento & purificação , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Brassica/economia , Células CACO-2 , Dióxido de Carbono/química , Diferenciação Celular , Proliferação de Células , Neoplasias Colorretais/dietoterapia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Suplementos Nutricionais/análise , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Isotiocianatos/análise , Isotiocianatos/isolamento & purificação , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Solventes/química , Esferoides Celulares , Sulfóxidos
5.
Molecules ; 21(4): 406, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-27023500

RESUMO

Oxidative stress is one of the key phenomena behind the most common types of chronic diseases. Therefore, the modulation of oxidative stress is an interesting target for acting either through prevention or as a therapeutic approach. In this work, a Portuguese variety of cherry (Saco Cherry) was processed in order to obtain a potent in vitro antioxidant phenolic-rich extract (Ch-PRE), which was further explored to evaluate its potential application as nutraceutical agent against cellular oxidative stress damage. Ch-PRE was mainly composed of anthocyanins, particularly cyanidin-3-rutinoside, cyanidin-3-glucoside, peonidin-3-glucoside and neochlorogenic acid, and exhibited a potent chemical antioxidant activity expressed by its oxygen radical absorbance capacity (ORAC) and hydroxyl radical averting capacity (HORAC) values. Ch-PRE also displayed effective intracellular radical scavenging properties in intestinal epithelial and neuronal cells challenged with oxidative stress but showed a different order of effectiveness regarding the modulation of endogenous antioxidant system. Ch-PRE could be an attractive candidate to formulate an agent for the prevention of oxidative stress-induced disorders such as intestinal inflammation disorders or with an appropriated delivery system for neurodegenerative diseases.


Assuntos
Antocianinas/química , Antioxidantes/química , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Antocianinas/farmacologia , Antioxidantes/farmacologia , Células CACO-2 , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Capacidade de Absorbância de Radicais de Oxigênio , Fenóis/farmacologia , Extratos Vegetais/química , Prunus avium/química
6.
Basic Clin Pharmacol Toxicol ; 116(5): 398-413, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25287116

RESUMO

Rosmarinic acid is a polyphenolic compound and main constituent of Rosmarinus officinalis and has been shown to possess antioxidant and anti-inflammatory properties. We aimed to evaluate the anti-inflammatory properties of rosmarinic acid and of an extract of R. officinalis in local inflammation (carrageenin-induced paw oedema model in the rat), and further evaluate the protective effect of rosmarinic acid in rat models of systemic inflammation: liver ischaemia-reperfusion (I/R) and thermal injury models. In the local inflammation model, rosmarinic acid was administered at 10, 25 and 50 mg/kg (p.o.), and the extract was administered at 10 and 25 mg/kg (equivalent doses to rosmarinic acid groups) to male Wistar rats. Administration of rosmarinic acid and extract at the dose of 25 mg/kg reduced paw oedema at 6 hr by over 60%, exhibiting a dose-response effect, suggesting that rosmarinic was the main contributor to the anti-inflammatory effect. In the liver I/R model, rosmarinic acid was administered at 25 mg/kg (i.v.) 30 min. prior to the induction of ischaemia and led to the significant reduction in the serum concentration of transaminases (AST and ALT) and LDH. In the thermal injury model, rosmarinic acid was administered at 25 mg/kg (i.v.) 5 min. prior to the induction of injury and significantly reduced multi-organ dysfunction markers (liver, kidney, lung) by modulating NF-κB and metalloproteinase-9. For the first time, the anti-inflammatory potential of rosmarinic acid has been identified, as it causes a substantial reduction in inflammation, and we speculate that it might be useful in the pharmacological modulation of injuries associated to inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Edema/prevenção & controle , Inflamação/prevenção & controle , Extratos Vegetais/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Rosmarinus , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/farmacologia , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Carragenina , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/sangue , Edema/induzido quimicamente , Edema/imunologia , Inflamação/sangue , Inflamação/etiologia , Inflamação/imunologia , Mediadores da Inflamação/sangue , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/imunologia , Explosão Respiratória/efeitos dos fármacos , Rosmarinus/química , Fatores de Tempo , Ácido Rosmarínico
7.
Food Chem ; 135(4): 2378-86, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22980816

RESUMO

Epidemiological evidence supports the concept that diets rich in fruits and vegetables promote health and attenuate or delay the onset of cardiovascular disease (CVD). In particular, a reduced risk of CVD has been associated with apple consumption, probably due to the cholesterol-lowering effect of the main bioactive compounds, namely fibre and polyphenols. In this work, the effect of diet supplementation with 20% of three Portuguese apple cultivars (Bravo de Esmolfe, Malápio Serra and Golden), containing distinct phenolic and fibre concentrations, on serum lipid profile and oxLDL of male Wistar rats fed a cholesterol-enriched diet (2%) was evaluated. After 30 days, only Bravo de Esmolfe apple was able to decrease significantly serum levels of triglycerides, total and LDL cholesterol concentrations (reductions of 27.2%, 21.0% and 20.4%, respectively, in relation to the cholesterol-enriched diet group, P<0.05). The levels of oxLDL were also significantly improved with the consumption of this apple variety (reductions of 20.0% and 11.9%, in relation to the cholesterol-enriched diet group and control group, respectively, P>0.05) as well as with Malapio da Serra apple (reductions of 9.8% in relation to the cholesterol-enriched diet group, P<0.05). Correlation of the bioactive response with chemical composition showed that catechin, epicatechin, procyanidin B1 and ß-carotene are the major phytocompounds responsible for the cholesterol lowering ability of apples. The antioxidant potential may have also contributed to this beneficial effect.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Malus/química , Extratos Vegetais/administração & dosagem , Animais , Doenças Cardiovasculares/tratamento farmacológico , Colesterol/sangue , Fibras na Dieta/administração & dosagem , Fibras na Dieta/análise , Humanos , Masculino , Extratos Vegetais/química , Ratos , Ratos Wistar , Triglicerídeos/sangue
8.
Int J Food Sci Nutr ; 61(4): 357-68, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20109126

RESUMO

To date there are no licensed systemic or topical treatments in Europe or the USA for adenovirus infections. In the present paper, we evaluate the effect of a polyphenol-based grape extract (NE) obtained from Portuguese white-winemaking by-products, and Resveratrol in pure form, on adenovirus type 5 infection. For this purpose, recombinant adenovirus vectors (Ad-5) and a human-derived cell line (293) were used as models. The NE and Resveratrol at the used concentrations do not induce cell cytotoxicity or direct virucidal activity; however, they reduce 4.5 and 6.5 log (TCID(50)/ml) on total infectious Ad-5 production, respectively. The capacity of Ad-5 replication upon removal of NE and Resveratrol after 24 h post infection was also evaluated. In contrast to Resveratrol, the highest evaluated NE concentration inhibits irreversibly the Ad-5 replication. These results provide useful information for the use of NE and Resveratrol as potential sources of promising natural antiviral agents on Ad-5 infection.


Assuntos
Adenoviridae/efeitos dos fármacos , Infecções por Adenovirus Humanos/tratamento farmacológico , Antivirais/uso terapêutico , Extratos Vegetais/uso terapêutico , Estilbenos/uso terapêutico , Vitis/química , Vinho , Adenoviridae/fisiologia , Antivirais/farmacologia , Linhagem Celular , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Indústria Alimentícia , Frutas , Vetores Genéticos , Humanos , Resíduos Industriais , Fenóis/farmacologia , Fenóis/uso terapêutico , Extratos Vegetais/farmacologia , Polifenóis , Portugal , Resveratrol , Estilbenos/farmacologia , Replicação Viral/efeitos dos fármacos
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