RESUMO
Hepatocellular carcinoma is the most common type of primary liver cancer. However, multidrug resistance (MDR) is a major obstacle to the effective chemotherapy of cancer cells. This report documents the rational design, synthesis, and biological evaluation of a novel series of triazolotriazines substituted with CH2NH-linked pyridine for use as dual c-Met/MDR inhibitors. Compound 12g with IC50 of 3.06 µM on HepG2 cells showed more potency than crizotinib (IC50 = 5.15 µM) in the MTT assay. In addition, 12g inhibited c-Met kinase at a low micromolar level (IC50 = 0.052 µM). 12g significantly inhibited P-gp and MRP1/2 efflux pumps in both cancerous HepG2 and BxPC3 cells starting from the lower concentrations of 3 and 0.3 µM, respectively. 12g did not inhibit MDR1 and MRP1/2 in noncancerous H69 cholangiocytes up to the concentration of 30 and 60 µM, respectively. Current results highlighted that cancerous cells were more susceptible to the effect of 12g than normal cells, in which the inhibition occurred only at the highest concentrations, suggesting a further interest in 12g as a selective anticancer agent. Overall, 12g, as a dual c-Met and P-gp/MRP inhibitor, is a promising lead compound for developing a new generation of anticancer agents.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Relação Estrutura-Atividade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Estrutura Molecular , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Triazinas/farmacologia , Triazinas/química , Triazinas/síntese químicaRESUMO
BACKGROUND: Cauliflower (Brassica oleracea L.) and globe artichoke (Cynara scolymus L.) are vegetables with a high waste index mainly related to stems and leaves. In this study, enzymatic hydrolysates obtained from these wastes were proposed to be used as plant biostimulants. Life cycle assessment methodology was also applied to evaluate environmental performances related to cauliflower and artichoke byproducts. RESULTS: Hydrolysates (HYs) were chemically and biologically characterized. Amino acids, organic acids, amines, polyols, mineral elements, phenols, tannins, flavonoids and sulfur compounds were identified and quantified by means of NMR, inductively coupled plasma mass spectrometry and UV-visible analyses. Cauliflower leaf and flower HYs showed the highest concentration of free amino acids, whereas stems showed the highest concentration of Ca. Regarding artichoke, asparagine, glutamine and aspartic acid were exclusively detected in stems, whereas artichoke leaves showed the highest Mg and Mn levels together with the highest antioxidant activity. The HYs diluted in water were tested as biostimulants. The impacts of five concentrations of HYs (0.00, 0.28, 0.84, 2.52 and 7.56 g L-1) on seed germination and early seedling growth of crimson clover, alfalfa, durum wheat and corn were investigated. CONCLUSIONS: The application of artichoke biostimulant (0.28 g L-1) positively influenced the coefficient of velocity of germination in alfalfa, crimson clover and durum wheat, whereas cauliflower biostimulant significantly improved corn germination speed. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
RESUMO
In the search for compounds that inhibit the SARS-CoV-2 after the onset of the COVID-19 pandemic, isoquinoline-containing alkaloids have been identified as compounds with high potential to fight the disease. In addition to having strong antiviral activities, most of these alkaloids have significant anti-inflammatory effects which are often manifested through the inhibition of a promising host-based anti-COVID-19 target, the p38 MAPK signaling pathway. In the present review, our pharmacological and medicinal chemistry evaluation resulted in highlighting the potential of anti-SARS-CoV-2 isoquinoline-based alkaloids for the treatment of COVID-19 patients. Considering critical parameters of the antiviral and anti-inflammatory activities, mechanism of action, as well as toxicity/safety profile, we introduce the alkaloids emetine, cephaeline, and papaverine as high-potential therapeutic agents for use in the treatment of COVID-19. Although preclinical studies confirm that some isoquinoline-based alkaloids reviewed in this study have a high potential to inhibit the SARS-CoV-2, their entry into drug regimens of COVID-19 patients requires further clinical trial studies and toxicity evaluation.
Assuntos
Alcaloides , COVID-19 , Humanos , Química Farmacêutica , SARS-CoV-2 , Pandemias , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêuticoRESUMO
Previous studies indicated that natural-based chalcones have significant inhibitory effects on the coronavirus enzymes 3CLpro and PLpro as well as modulation of some host-based antiviral targets (HBATs). In this study, a comprehensive computational and structural study was performed to investigate the affinity of our compound library consisting of 757 chalcone-based structures (CHA-1 to CHA-757) for inhibiting the 3CLpro and PLpro enzymes and against twelve selected host-based targets. Our results indicated that CHA-12 (VUF 4819) is the most potent and multi-target inhibitor in our chemical library over all viral and host-based targets. Correspondingly, CHA-384 and its congeners containing ureide moieties were found to be potent and selective 3CLpro inhibitors, and benzotriazole moiety in CHA-37 was found to be a main fragment for inhibiting the 3CLpro and PLpro. Surprisingly, our results indicate that the ureide and sulfonamide moieties are integral fragments for the optimum 3CLpro inhibition while occupying the S1 and S3 subsites, which is fully consistent with recent reports on the site-specific 3CLpro inhibitors. Finding the multi-target inhibitor CHA-12, previously reported as an LTD4 antagonist for the treatment of inflammatory pulmonary diseases, prompted us to suggest it as a concomitant agent for relieving respiratory symptoms and suppressing COVID-19 infection.
Assuntos
COVID-19 , Chalcona , Chalconas , Humanos , SARS-CoV-2 , Chalconas/farmacologia , Chalcona/farmacologia , Cisteína Endopeptidases/química , Antivirais/farmacologia , Antivirais/química , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , Inibidores de Proteases/químicaRESUMO
In this work, for the first time, a gruyt beer and the same one after the addition of Citrus aurantium essential oil (AEO), were investigated to determine the composition of the volatile fraction. The applied analytical techniques, such as Head Space/Solid Phase Microextraction-Gas Chromatography-Mass Spectrometry (HS/SPME-GC-MS) and Proton Transfer Reaction-Time of Flight-Mass Spectrometer (PTR-ToF-MS), allowed us to identify the content of volatile organic compounds (VOCs). From the comparison between the two beer samples, it showed that the one after the addition of AEO was particularly richened in limonene and a series of minor terpene compounds. AEO was also characterized by GC/MS analysis and the results showed that limonene reached 95%. Confocal microscopy was used to look at riboflavin autofluorescence in yeast cells. It was found that beer with AEO had twice as much fluorescence intensity as the control. A spectrophotometric analysis of total polyphenols, tannins, and flavonoids, and a bioactivity screening, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-Azinobis-(3-Ethylbenzthiazolin-6-Sulfonic Acid) (ABTS) radical scavenger, chelating, reducing, antiglycative ones, were also carried out. Moreover, the tolerability of the tested samples in human H69 cholangiocytes and the cytoprotection towards the tert-butyl hydroperoxide (tBOOH)-induced oxidative damage were evaluated. Under our experimental conditions, the beers were found to be able to scavenge DPPH and ABTS radicals and chelate iron ions, despite weak antiglycative and reducing properties. The tested samples did not affect the viability of H69 cholangiocytes up to the highest concentrations; moreover, no signs of cytoprotection against the damage induced by tBOOH were highlighted. Adding AEO to beer resulted in a moderate enhancement of its DPPH scavenging and chelating abilities, without improvements in the other assays. Conversely, AEO and its major compound limonene were ineffective when assessed at the concentrations added to beer. This evidence suggests that the addition of AEO may enhance the organoleptic features of the beer and slightly potentiate some of its bioactivities.
Assuntos
Benzotiazóis , Compostos de Bifenilo , Citrus , Óleos Voláteis , Ácidos Sulfônicos , Humanos , Óleos Voláteis/farmacologia , Limoneno , CervejaRESUMO
In the present study, the phytochemical composition and bioactivities of A. maroccanus (AM) and A. radiatus (AR), two ecotypes collected in the Demnate road and Essaouira regions, respectively, were studied to highlight a pharmacological interest and to enable possible pharmaceutical development. To this end, methanolic and ethyl acetate extracts were prepared for each ecotype by fractionation; next, their phytochemical composition was evaluated by spectrophotometric and chromatographic analysis. Moreover, in line with the available evidence for Anacyclus spp. and their traditional use, a screening of bioactivities, including antioxidant, hypoglycemic, antiglycative, chelating, and antibacterial activities, was performed. The extracts were characterized by high amounts of polyphenols, tannins, and flavonoids, especially in the methanolic extracts; these samples were also enriched in carotenoids despite a lower chlorophyll content. Chlorogenic acid and rutin were the major identified compounds. The extracts also showed interesting hypoglycemic, antiglycative, and antibacterial properties, although with differences in efficacy and potency. Present results provide more scientific basis to the ethnopharmacological uses of Anacyclus spp. and suggest a further interest in AM and AR ecotypes as natural sources of bioactive compounds and/or phytocomplexes for possible pharmaceutical and nutraceutical developments.
Assuntos
Asteraceae/genética , Asteraceae/metabolismo , Compostos Fitoquímicos/análise , Antibacterianos/farmacologia , Antioxidantes/química , Asteraceae/efeitos dos fármacos , Flavonoides/análise , Testes de Sensibilidade Microbiana , Marrocos , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Polifenóis/química , TaninosRESUMO
Cannabis sativa L. crops have been traditionally exploited as sources of fibers, nutrients, and bioactive phytochemicals of medical interest. In the present study, two terpene-rich organic extracts, namely FOJ and FOS, obtained from Felina 32 hemp inflorescences collected in June and September, respectively, have been studied for their in vitro anticancer properties. Particularly, their cytotoxicity was evaluated in different cancer cell lines, and the possible entourage effect between nonintoxicating phytocannabinoids (cannabidiol and cannabichromene) and caryophyllane sesquiterpenes (ß-caryophyllene, ß-caryophyllene oxide and α-humulene), as identified at GC/MS analysis, was characterized. Modulation of cannabinoid CB1 and CB2 receptors was studied as a mechanistic hypothesis. Results highlighted marked cytotoxic effects of FOJ, FOS, and pure compounds in triple negative breast cancer MDA-MB-468 cells, likely mediated by a CB2 receptor activation. Cannabidiol was the main cytotoxic constituent, although low levels of caryophyllane sesquiterpenes and cannabichromene induced potentiating effects; the presence in the extracts of unknown antagonistic compounds has been highlighted too. These results suggest an interest in Felina 32 hemp inflorescences as a source of bioactive phytocomplexes with anticancer properties and strengthen the importance of considering the possible involvement of minor terpenes, such as caryophyllane sesquiterpenes, in the entourage effect of hemp-based extracts.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Inflorescência/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Sesquiterpenos Policíclicos/farmacologia , Antineoplásicos Fitogênicos/química , Cannabis/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Sesquiterpenos Monocíclicos/química , Sesquiterpenos Monocíclicos/farmacologia , Compostos Fitoquímicos/química , Extratos Vegetais/química , Sesquiterpenos Policíclicos/química , Receptor CB2 de Canabinoide/metabolismo , Neoplasias de Mama Triplo NegativasRESUMO
Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes ß-caryophyllene and ß-caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2-chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that ß-caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose , Carcinoma Hepatocelular/patologia , Doxorrubicina/farmacologia , Neoplasias Hepáticas/patologia , Sesquiterpenos Policíclicos/química , Sesquiterpenos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antibióticos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Células Tumorais CultivadasRESUMO
The chemical composition of the inflorescences from four Cannabis sativa L. monoecious cultivars (Ferimon, Uso-31, Felina 32 and Fedora 17), recently introduced in the Lazio Region, was monitored over the season from June to September giving indications on their sensorial, pharmaceutical/nutraceutical proprieties. Both untargeted (NMR) and targeted (GC/MS, UHPLC, HPLC-PDA/FD and spectrophotometry) analyses were carried out to identify and quantify compounds of different classes (sugars, organic acids, amino acids, cannabinoids, terpenoids, phenols, tannins, flavonoids and biogenic amines). All cultivars in each harvesting period showed a THC content below the Italian legal limit, although in general THC content increased over the season. Citric acid, malic acid and glucose showed the highest content in the late flowering period, whereas the content of proline drastically decreased after June in all cultivars. Neophytadiene, nerolidol and chlorogenic acid were quantified only in Felina 32 cultivar, characterized also by a very high content of flavonoids, whereas alloaromadendrene and trans-cinnamic acid were detected only in Uso-31 cultivar. Naringenin and naringin were present only in Fedora 17 and Ferimon cultivars, respectively. Moreover, Ferimon had the highest concentration of biogenic amines, especially in July and August. Cadaverine was present in all cultivars but only in September. These results suggest that the chemical composition of Cannabis sativa L. inflorescences depends on the cultivar and on the harvesting period. Producers can use this information as a guide to obtain inflorescences with peculiar chemical characteristics according to the specific use.
Assuntos
Cannabis/química , Cannabis/crescimento & desenvolvimento , Inflorescência/química , Canabinoides/química , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Flores/química , Cromatografia Gasosa-Espectrometria de Massas , Itália , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Desenvolvimento VegetalRESUMO
Several ATP-binding cassette (ABC) proteins reduce intracellular concentrations of antitumor drugs and hence weaken the response of cancer cells to chemotherapy. Accordingly, the inhibition of these export pumps constitutes a promising strategy to chemosensitize highly chemoresistant tumors, such as hepatocellular carcinoma (HCC). Here, we have investigated the ability of ß-caryophyllene oxide (CRYO), a naturally occurring sesquiterpene component of many essential oils, to inhibit, at non-toxic doses, ABC pumps and improve the response of HCC cells to sorafenib. First, we have obtained a clonal subline (Alexander/R) derived from human hepatoma cells with enhanced multidrug resistance (MDR) associated to up-regulation (mRNA and protein) of MRP1 and MRP2. Analysis of fluorescent substrates export (flow cytometry) revealed that CRYO did not affect the efflux of fluorescein (MRP3, MRP4 and MRP5) but inhibited that of rhodamine 123 (MDR1) and calcein (MRP1 and MRP2). This ability was higher for CRYO than for other sesquiterpenes assayed. CRYO also inhibited sorafenib efflux, increased its intracellular accumulation (HPLC-MS/MS) and enhanced its cytotoxic response (MTT). For comparison, the effect of known ABC pumps inhibitors was also determined. They induced strong (diclofenac on MRPs), modest (verapamil on MDR1) or null (fumitremorgin C on BCRP) effect on sorafenib efflux and cytotoxicity. In the mouse xenograft model, the response to sorafenib treatment of subcutaneous tumors generated by mouse hepatoma Hepa 1-6/R cells, with marked MDR phenotype, was significantly enhanced by CRYO co-administration. In conclusion, at non-toxic dose, CRYO is able to chemosensitizating liver cancer cells to sorafenib by favoring its intracellular accumulation.
Assuntos
Antineoplásicos/toxicidade , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sesquiterpenos Policíclicos/metabolismo , Sorafenibe/toxicidade , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Humanos , Neoplasias Hepáticas , Camundongos , Proteínas de NeoplasiasRESUMO
Pomegranate peel is a natural source of phenolics, claimed to possess healing properties, among which are antioxidant and antidiabetic. In the present study, an ethyl acetate extract, obtained by Soxhlet from the peel of Dente di Cavallo DC2 pomegranate (PGE) and characterized to contain 4% w/w of ellagic acid, has been evaluated for its hypoglycemic, antiglycation, and antioxidative cytoprotective properties, in order to provide possible evidence for future nutraceutical applications. The α-amylase and α-glucosidase enzyme inhibition, interference with advanced glycation end-products (AGE) formation, and metal chelating abilities were studied. Moreover, the possible antioxidant cytoprotective properties of PGE under hyperglycemic conditions were assayed. Phenolic profile of the extract was characterized by integrated chromatographic and spectrophotometric methods. PGE resulted able to strongly inhibit the tested enzymes, especially α-glucosidase, and exerted chelating and antiglycation properties. Also, it counteracted the intracellular oxidative stress under hyperglycemic conditions, by reducing the levels of reactive oxygen species and total glutathione. Among the identified phenolics, rutin was the most abundant flavonoid (about 4 % w/w). Present results suggest PGE to be a possible remedy for hyperglycemia management and encourage further studies to exploit its promising properties.
Assuntos
Antioxidantes/química , Hipoglicemiantes/química , Fenóis/química , Punica granatum/química , Antioxidantes/farmacologia , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Glutationa/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Fenóis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rutina/química , Rutina/farmacologia , alfa-Amilases/antagonistas & inibidoresRESUMO
DR2B and DR2C extracts, obtained by ethanolic maceration of peel from commercially and physiologically ripe aubergine berries, were studied for the antioxidative cytoprotective properties and anti-HSV-1 activity, in line with the evidence that several antioxidants can impair viral replication by maintaining reducing conditions in host cells. The antioxidative cytoprotective effects against tBOOH-induced damage were assessed in Caco2 cells, while antiviral activity was studied in Vero cells; polyphenolic fingerprints were characterized by integrated phytochemical methods. Results highlighted different compositions of the extracts, with chlorogenic acid and delphinidin-3-rutinoside as the major constituents; other peculiar phytochemicals were also identified. Both samples reduced reactive oxygen species (ROS) production and exhibited scavenging and chelating properties. DR2C partly counteracted the tBOOH-induced cytotoxicity, with a remarkable lowering of lactate metabolism under both normoxia and hypoxia; interestingly, it increased intracellular GSH levels. Furthermore, DR2C inhibited the HSV-1 replication when added for 24 h after viral adsorption, as also confirmed by the reduction of many viral proteins' expression. Since DR2C was able to reduce NOX4 expression during HSV-1 infection, its antiviral activity may be correlated to its antioxidant properties. Although further studies are needed to better characterize DR2C activity, the results suggest this extract as a promising new anti-HSV-1 agent.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Antivirais/química , Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Solanum melongena/química , Animais , Antocianinas/química , Antocianinas/farmacologia , Linhagem Celular , Células Cultivadas , Quelantes/química , Quelantes/farmacologia , Cromatografia Líquida de Alta Pressão , Citoproteção , Flavonoides/química , Flavonoides/farmacologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
Due to renewed interest in the cultivation and production of Italian Cannabis sativa L., we proposed a multi-methodological approach to explore chemically and biologically both the essential oil and the aromatic water of this plant. We reported the chemical composition in terms of cannabinoid content, volatile component, phenolic and flavonoid pattern, and color characteristics. Then, we demonstrated the ethnopharmacological relevance of this plant cultivated in Italy as a source of antioxidant compounds toward a large panel of enzymes (pancreatic lipase, α-amylase, α-glucosidase, and cholinesterases) and selected clinically relevant, multidrug-sensible, and multidrug-resistant microbial strains (Staphylococcus aureus, Helicobacter pylori, Candida, and Malassezia spp.), evaluating the cytotoxic effects against normal and malignant cell lines. Preliminary in vivo cytotoxicity was also performed on Galleria mellonella larvae. The results corroborate the use of this natural product as a rich source of important biologically active molecules with particular emphasis on the role exerted by naringenin, one of the most important secondary metabolites.
Assuntos
Cannabis/química , Flavonoides/química , Flavonoides/farmacologia , Óleos Voláteis/análise , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Células CACO-2 , Linhagem Celular Tumoral , Etnofarmacologia , Humanos , Itália , Células MCF-7 , Testes de Sensibilidade Microbiana , Óleos Voláteis/farmacologia , Fenóis/química , Fenóis/farmacologia , Plâncton/efeitos dos fármacosRESUMO
One Sisymbrium officinale (L.) Scop. aqueous dry extract (SOE) and its polyphenolic fractions (Fb, Fc, Fd and Fe) were evaluated for their ability to inhibit the oxidative mutagenicity of tert-butylhydroperoxide in the Ames test. The possible involvement of desmutagenic and/or bioantimutagenic mechanisms was evaluated by applying a three-time based protocol (pre-treatment, co-treatment and post-treatment). Furthermore, some protective antioxidant mechanisms were investigated. The total polyphenol and flavonol amount was also determined, and the fingerprint was outlined by high-performance thin-layer chromatography and densitometry. SOE, Fb and Fe exhibited strong antimutagenicity against tert-butylhydroperoxide in all treatment protocols, this suggesting the involvement of both desmutagenic and bioantimutagenic mechanisms. These samples also showed antioxidant properties, including neutralization of the superoxide anion, lipid peroxidation inhibition and chelation and reduction of iron. Fb and Fe were rich in polyphenols and flavonols, so suggesting a possible role of these compounds in the antimutagenicity. Taking into account that oxidative stress is responsible for the damage of various environmental toxicants, particularly tobacco smoke, present results can support the traditional use of hedge mustard by smokers to restore the vocal cord function affected by the oxidative damage and suggest a possible application of SOE and its fractions as food supplements. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Brassicaceae/química , Escherichia coli/efeitos dos fármacos , Extratos Vegetais/química , terc-Butil Hidroperóxido/química , Antioxidantes , MutagênicosRESUMO
Cigarette filters pose a serious litter and toxic waste disposal problem, because of their not biodegradability and to the leaching of toxins in the environment. Therefore, cigarette butts need to be manipulated as special waste, with potential risks to human health and environment. In the present study, the genotoxic potential of a methanol extract from commonly discharged cigarette butts (CBE) was evaluated in the bacterial reverse mutation assay on Salmonella typhimurium TA98 and TA100 and Escherichia coli WP2uvrA strains, both in the absence and presence of the S9 exogenous metabolic activator. Furthermore, the ability of the natural sesquiterpenes ß-caryophyllene (CRY) and ß-caryophyllene oxide (CRYO) to inhibit the mutagenicity of CBE was studied as a possible preventive strategy. In order to identify the potential antimutagenic mechanisms, three different protocols (pretreatment, cotreatment, and posttreatment) were applied. CBE showed to increase the number of revertant colonies in all the strains tested in presence of S9, so resulting mutagenic. In the antimutagenicity assay, both CRY and CRYO significantly reduced the revertant colonies induced by CBE, although with different potency and specificity. For both sesquiterpenes, the antimutagenicity was strong in all experimental conditions, except for the cotreatment of CRY with CBE in WP2uvrA, which produced a moderate inhibition. Both desmutagenic and bioantimutagenic mechanisms seem to be involved in the antimutagenicity of the test substances. Taking into account the potential genotoxicity of cigarette butts, CRY and CRYO appear as possible further candidates as environmental decontaminants against this hazardous waste. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1319-1328, 2016.
Assuntos
Substâncias Protetoras/farmacologia , Salmonella typhimurium/efeitos dos fármacos , Sesquiterpenos/farmacologia , Produtos do Tabaco/análise , Bioensaio , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Humanos , Testes de Mutagenicidade , Sesquiterpenos Policíclicos , Salmonella typhimurium/genéticaRESUMO
The ability of the naturally derived compound α-hexylcinnamaldehyde (1) to interact with biomembranes and to modulate their permeability has been investigated as a strategy to reverse multidrug resistance (MDR) in cancer cells. Dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLVs) were used as biomembrane models, and differential scanning calorimetry was applied to measure the effect of 1 on the thermotropic behavior of DMPC MLVs. The effect of an aqueous medium or a lipid carrier on the uptake of 1 by the biomembrane was also characterized. Furthermore, taking into account that MDR is strictly regulated by redox signaling, the pro-oxidant and/or antioxidant effects of 1 were evaluated by the crocin-bleaching assay, in both hydrophilic and lipophilic environments. Compound 1 was uniformly distributed in the phospholipid bilayers and deeply interacted with DMPC MLVs, intercalating among the phospholipid acyl chains and thus decreasing their cooperativity. The lipophilic medium allowed the absorption of 1 into the phospholipid membrane. In the crocin-bleaching assay, the substance produced no pro-oxidant effects in both hydrophilic and lipophilic environments; conversely, a significant inhibition of AAPH-induced oxidation was exerted in hydrophilic medium. These results suggest a possible role of 1 as a chemopreventive and chemosensitizing agent for fighting cancer.
Assuntos
Acroleína/análogos & derivados , Resistência a Múltiplos Medicamentos/fisiologia , Modelos Biológicos , Acroleína/química , Varredura Diferencial de Calorimetria , Dimiristoilfosfatidilcolina/química , Estrutura Molecular , Fosfolipídeos/químicaRESUMO
Green tea (GT), obtained from the leaves of Camellia sinensis (L.) Kuntze (Fam. Theaceae), is largely used for its potential health benefits such as reduction in risk of cardiovascular diseases and weight loss. Nevertheless, it is suspected to induce liver damage. Present work reviews the hepatic adverse reactions associated with GT-based herbal supplements, published by the end of 2008 to March 2015. A systematic research was carried out on PubMed, MedlinePlus, Scopus and Google Scholar databases, without any language restriction. Moreover, some accessible databases on pharmacovigilance or phytovigilance were consulted. The causality assessment was performed using the CIOMS/RUCAM score. Nineteen cases of hepatotoxicity related to the consumption of herbal products containing GT were identified. The hepatic reactions involved mostly women (16/19); the kind of liver damage was generally classified as hepatocellular (16/19). The causality assessment between consumption of herbal preparation and hepatic reaction resulted as probable in eight cases and as possible in eleven cases. In seven cases, patients used preparations containing only GT, while twelve reactions involved patients who took multicomponent preparations (MC). The reactions induced by GT had a generally long latency (179.1 ± 58.95 days), and the outcome was always resolution, with recovery time of 64.6 ± 17.78 days. On the contrary, liver injury associated with MC had a shorter latency (44.7 ± 13.85 days) and was more serious in four cases that required liver transplantation and, when resolution occurred, the recovery time was longer (118.9 ± 38.79). MC preparations contained numerous other components, many of which are suspected to induce liver damage, so it is difficult to ascribe the toxicity to one specific component, e.g., GT. Present data confirm a certain safety concern with GT, even if the number of hepatic reactions reported is low considering the great extent of use of this supplement. The mechanism of GT hepatotoxicity remains unclear, but factors related to the patient are becoming predominant. A major safety concern exists when GT is associated with other ingredients that can interact between them and with GT, enhancing the risk of liver damage. Patients should be discouraged from using herbal or dietary supplements containing complex mixtures and should be encouraged to use herbal and dietary supplement possibly under supervision of healthcare professionals.
Assuntos
Camellia sinensis/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Suplementos Nutricionais/toxicidade , Chá/toxicidade , Chás de Ervas/toxicidade , Camellia sinensis/química , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , Qualidade de Produtos para o Consumidor , HumanosRESUMO
A comprehensive study on essential oils (EOs) extracted from some Mentha suaveolens L. samples, collected in the countryside of Tarquinia, is reported. In this study, the procedure for essential oil preparation, in terms of harvesting and extraction time, was analyzed in detail for the first time. The GC/MS analysis, carried out on 18 samples, revealed that piperitenone oxide (PO), the main essential oils' chemical constituent, is primarily responsible for the related antifungal activity. Nevertheless, EOs with lower PO content indicate that other chemicals, such as para-cymenene, may participate in exerting the EOs' antifungal effect. Furthermore, the bacterial reverse mutation assay highlighted lack of mutagenic effect in all tested samples. Analysis of the results indicated that for higher activity, the essential oils should be produced with 3 h maximum hydrodistillation, regardless of the harvesting time. Differently, the maximum essential oil yield can be obtained in August and the highest piperitenone oxide percentage is obtainable in July.
Assuntos
Antifúngicos/isolamento & purificação , Mentha/química , Monoterpenos/isolamento & purificação , Óleos Voláteis/isolamento & purificação , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Cromatografia Gasosa-Espectrometria de Massas , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Monoterpenos/farmacologia , Mutação , Óleos Voláteis/farmacologia , Óxidos , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Estações do Ano , Extração em Fase Sólida/métodos , Fatores de TempoRESUMO
CONTEXT: Urtica dioica L. (Urticaceae), stinging nettle, has been employed as a folklore remedy for a wide spectrum of ailments, including urinary disorders, prostatic hyperplasia, and liver diseases. It has been also used traditionally for cancer treatment. OBJECT: To evaluate the potential chemopreventive properties of a protein fraction from the aerial part of Urtica dioica (namely UDHL30). MATERIALS AND METHODS: UDHL30 has been tested for the antimutagenic activity in bacteria (50-800 µg/plate; Ames test by the preincubation method) and for the cytotoxicity on human hepatoma HepG2 cells (0.06-2 mg/mL; 24 and 48 h incubation). Moreover, the antioxidant activity of UDHL30 (0.1-1200 µg/mL; ABTS and superoxide-radical scavenger assays) was evaluated as potential protective mechanisms. RESULTS: UDHL30 was not cytotoxic on HepG2 cells up to 2 mg/mL; conversely, it exhibited a strong antimutagenic activity against the mutagen 2-aminoanthracene (2AA) in all strains tested (maximum inhibition of 56, 78, and 61% in TA98, TA100, and WP2uvrA strains, respectively, at 800 µg/plate). In addition, a remarkable scavenging activity against ABTS radical and superoxide anion (IC50 values of 19.9 ± 1.0 µg/mL and 75.3 ± 0.9 µg/mL, respectively) was produced. DISCUSSION AND CONCLUSIONS: UDHL30 possesses antimutagenic and radical scavenging properties. Being 2AA a pro-carcinogenic agent, we hypothesize that the antimutagenicity of UDHL30 can be due to the inhibition of CYP450-isoenzymes, involved in the mutagen bioactivation. The radical scavenger ability could contribute to 2AA-antimutagenicity. These data encourage further studies in order to better define the potential usefulness of UDHL30 in chemoprevention.
Assuntos
Antimutagênicos/farmacologia , Antioxidantes/farmacologia , Proteínas de Plantas/farmacologia , Urtica dioica/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/farmacologia , Humanos , Testes de Mutagenicidade , Folhas de Planta/químicaRESUMO
The maternal separation protocol in rodents is a widely recognized model of early life stress allowing acute and chronic physiological consequences to be studied. An (1)H NMR-based metabolomic approach was applied to urines to evaluate the systemic metabolic consequences of maternal separation stress in female rats after the beginning of weaning and 4 weeks later when the rats were reaching adulthood. Furthermore, because maternal separation is considered as a model mimicking the inflammatory bowel syndrome, the lactulose/mannitol test was used to evaluate the influence of postnatal maternal separation on gut permeability and mucosal barrier function by (1)H NMR spectroscopy analysis of urine. The results showed no statistical differences in gut permeability due to maternal separation. The application of ANOVA simultaneous component analysis allowed the contributions of physiological adaptations to the animal's development to be separated from the metabolic consequences due to postnatal stress. Systemic metabolic differences in the maternally separated pups were mainly due to the tryptophan/NAD pathway intermediate levels and to the methyladenosine level. Urinary NMR-based metabolic profiling allowed us to disentangle the metabolic adaptive response of the rats to postnatal stress during the animal's growth, highlighting the metabolic changes induced by weaning, gut closure, and maturity.