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1.
Artigo em Inglês | MEDLINE | ID: mdl-34339956

RESUMO

Ylang-ylang (YY) essential oil (EO) is distilled from the fresh-mature flowers of the Annonaceae family tropical tree Cananga odorata [Lam.] Hook. f. & Thomson, and is widely used in perfume and cosmetic industries for its fragrant character. Herein, two different metabolomic profiles obtained using high-performance thin-layer chromatography (HPTLC), applying different stains, namely 2,2-diphenyl-1-picrylhydrazyl (DPPH·) and p-anisaldehyde, were used for discrimination of 52 YY samples across geographical origins and distillation grades. The first profile is developed using the DPPH· stain based on the radical scavenging activity (RSA) of YY EOs. Results of the HPTLC-DPPH· assay confirmed that RSA of YY EOs is in proportion to the length of distillation times. Major components contributing to the RSA of YY EOs were tentatively identified as germacrene D and α-farnesene, eugenol and linalool, by gas chromatography-mass spectrometry (GC-MS) and GC-flame ionisation detector (GC-FID). The second profile was developed using the general-purpose p-anisaldehyde stain based on the general chemical composition of YY EOs. Untargeted metabolomic discrimination of YY EOs from different geographical origins was performed based on the HPTLC-p-anisaldehyde profiles, followed by principal component analysis (PCA). A discrimination and prediction model for identification of YY distillation grade was developed using PCA and partial least squares regression (PLS) based on binned HPTLC-ultraviolet (254 nm) profiles, which was successfully applied to distillation grade determination of blended YY Complete EOs.


Assuntos
Cananga/química , Cromatografia em Camada Delgada/métodos , Sequestradores de Radicais Livres/química , Óleos Voláteis/química , Óleos Vegetais/química , Compostos de Bifenilo/análise , Compostos de Bifenilo/metabolismo , Cromatografia Líquida de Alta Pressão , Destilação , Eugenol/análise , Eugenol/química , Eugenol/metabolismo , Sequestradores de Radicais Livres/metabolismo , Metabolômica , Análise Multivariada , Óleos Voláteis/metabolismo , Picratos/análise , Picratos/metabolismo , Óleos Vegetais/metabolismo , Sesquiterpenos/análise , Sesquiterpenos/química , Sesquiterpenos/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445416

RESUMO

The antioxidant and anti-inflammatory potentials of polyphenols contained in Gynura procumbens (GP) extract were systematically analyzed. Polyphenols in GP were analyzed for nine peaks using high-performance liquid chromatography (HPLC) combined with mass spectrometry (MS), and quantitatively determined through each standard. A total of nine polyphenolic compounds were identified in the samples and their MS data were tabulated. To determine the potential of bioactive ingredients targeting DPPH and COX-2, we analyzed them by ultrafiltration combined with LC. The results identified the major compounds exhibiting binding affinity for DPPH and COX-2. Caffeic acid, kynurenic acid, and chlorogenic acid showed excellent binding affinity to DPPH and COX-2, suggesting that they can be considered as major active compounds. Additionally, the anti-inflammatory effect of GP was confirmed in vitro. This study will not only be used to provide basic data for the application of GP to the food and pharmaceutical industries, but will also provide information on effective screening methods for other medicinal plants.


Assuntos
Anti-Inflamatórios/análise , Antioxidantes/análise , Asteraceae/química , Ciclo-Oxigenase 2/metabolismo , Polifenóis/análise , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Compostos de Bifenilo/metabolismo , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Lipopolissacarídeos/efeitos adversos , Espectrometria de Massas , Camundongos , Picratos/metabolismo , Extratos Vegetais/química , Polifenóis/farmacologia , Células RAW 264.7
3.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200647

RESUMO

Curcuminoids are the main bioactive components of the well-known Asian spice and traditional medicine turmeric. Curcuminoids have poor chemical stability and bioavailability; in vivo they are rapidly metabolized to a set of bioreduced derivatives and/or glucuronide and sulfate conjugates. The reduced curcuminoid metabolites were also reported to exert various bioactivities in vitro and in vivo. In this work, we aimed to perform a comparative evaluation of curcuminoids and their hydrogenated metabolites from a medicinal chemistry point of view, by determining a set of key pharmacokinetic parameters and evaluating antioxidant potential in relation to such properties.Reduced metabolites were prepared from curcumin and demethoxycurcumin through continuous-flow hydrogenation. As selected pharmacokinetic parameters, kinetic solubility, chemical stability, metabolic stability in human liver microsomes, and parallel artificial membrane permeability assay (PAMPA)-based gastrointestinal and blood-brain barrier permeability were determined. Experimentally determined logP for hydrocurcumins in octanol-water and toluene-water systems provided valuable data on the tendency for intramolecular hydrogen bonding by these compounds. Drug likeness of the compounds were further evaluated by a in silico calculations. Antioxidant properties in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and oxygen radical absorbance capacity (ORAC) assays were comparatively evaluated through the determination of ligand lipophilic efficiency (LLE). Our results showed dramatically increased water solubility and chemical stability for the reduced metabolites as compared to their corresponding parent compound. Hexahydrocurcumin was found the best candidate for drug development based on a complex pharmacokinetical comparison and high LLE values for its antioxidant properties. Development of tetrahydrocurcumin and tetrahydro-demethoxycurcumin would be limited by their very poor metabolic stability, therefore such an effort would rely on formulations bypassing first-pass metabolism.


Assuntos
Antioxidantes/farmacologia , Antioxidantes/farmacocinética , Diarileptanoides/farmacologia , Diarileptanoides/farmacocinética , Disponibilidade Biológica , Compostos de Bifenilo/metabolismo , Permeabilidade da Membrana Celular/fisiologia , Química Farmacêutica , Curcuma/metabolismo , Curcumina/análogos & derivados , Curcumina/metabolismo , Glucuronídeos/metabolismo , Humanos , Hidrogenação , Microssomos Hepáticos/metabolismo , Picratos/metabolismo , Solubilidade
4.
Acta Sci Pol Technol Aliment ; 20(3): 253-263, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34304544

RESUMO

BACKGROUND: The diet of most of the population is limited to a reduced number of plants, even in areas that have a varied and extensive diversity, such as Brazil. Unconventional Food Plants (UFPs) are plants considered exotic, native, and wild that grow naturally and can be used as food. Among these is Talinum paniculatum (Jacq.) Gaertn., which is widespread throughout Brazil and can be a potential source of nutrients. Due to the potential of utilization of UFPs in human food and the lack of studies regarding the composition of T. paniculatum, this study aimed to assess the nutritional value of T. paniculatum leaves, their antioxidant capacity, and their antimicrobial activity for possible use in food. METHODS: The characterization of the leaves of T. paniculatum was carried out through analyses of proximal composition, color, ascorbic acid, mineral profile, and antinutritional factors showing the presence of condensed and hydrolysable tannins and nitrates in low concentrations. Solvents of water, ethanol, ethanol/water, methanol, methanol/water, methanol/acetic acid and acetone/water/acetic acid were used to evaluate the extraction yield of phenolic compounds, antioxidant capacity, and antibacterial activity of the extracts. RESULTS: High contents of protein (18.61 g 100 g-1), insoluble dietary fiber (34.75 g 100 g-1), ascorbic acid (81.03 mg 100 g-1), magnesium, potassium, and calcium (649.600, 411.520 and 228.117 mg 100 g-1, respectively) were observed. Extraction using the mixture of solvents of methanol/acetic acid showed the highest yield of phenolic compounds (432.73 mg EAG 100 g-1) and antioxidant capacity using the DPPH assay (3144.92 mg 100 g-1). Bacillus cereus growth was inhibited by the T. paniculatum extracts. CONCLUSIONS: T. paniculatum leaves are a source of nutrients and their extracts have antioxidant and antibacterial potentials which can be used as supplements in food to improve one's health.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Caryophyllales/química , Nutrientes/análise , Valor Nutritivo , Extratos Vegetais/farmacologia , Folhas de Planta/química , Antibacterianos/análise , Antioxidantes/análise , Bacillus cereus/efeitos dos fármacos , Bacillus cereus/crescimento & desenvolvimento , Compostos de Bifenilo/metabolismo , Brasil , Dieta , Fenóis/análise , Fenóis/farmacologia , Picratos/metabolismo , Extratos Vegetais/química , Plantas Comestíveis/química
5.
Acta Sci Pol Technol Aliment ; 20(3): 277-290, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34304546

RESUMO

BACKGROUND: The globe artichoke (Cynara scolymus L.) is a rich source of phenolic compounds which may be extracted by ultrasound technology and used as a medicinal alternative. The objective of this work was to determine the radiation amplitude (%), ethanol concentration (%), and time extraction (min) required to guarantee an elevated content of polyphenol compounds. METHODS: The optimal extraction conditions were assessed through the Box-Wilson design and by applying Composite Face Centered (CCFC) and total phenolic compounds (TPC) as the response variables. RESULTS: A quadratic model was adequate, with R2 = 0.993. The optimal conditions were a radiation amplitude of 97%, an ethanol concentration of 53%, and an extraction time of 9.7 min. The optimized extract of artichoke bracts (Cynara scolymus L.) showed a TPC of 25.13 (±0.030) mg GAE/g, an antioxidant activity DPPH of 39.79 (±0.014) mmol Trolox equivalents (TE), and an antioxidant capacity TEAC of 33.98 (±0.03) mmol Trolox equivalents. CONCLUSIONS: The results showed values closely related to the expected values, indicating that the models were well-developed.


Assuntos
Antioxidantes/análise , Cynara scolymus/química , Extratos Vegetais/química , Polifenóis/análise , Tecnologia Farmacêutica/métodos , Antioxidantes/farmacologia , Compostos de Bifenilo/metabolismo , Composição de Medicamentos , Etanol , Modelos Biológicos , Fenóis/análise , Fenóis/farmacologia , Fitoterapia , Picratos/metabolismo , Extratos Vegetais/farmacologia , Folhas de Planta/química , Polifenóis/farmacologia
6.
Fish Physiol Biochem ; 47(4): 1073-1085, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34021418

RESUMO

In this study, substance P, an antioxidant peptide of tachykinin, was identified using bioinformatics tools from the earlier established muscle transcriptome of a freshwater murrel Channa striatus and the peptide was named RM12. The antioxidant properties of RM12 were screened using various colorimetric assays. The toxicity of RM12 was experimented using fish erythrocytes, and it is observed that the maximum concentration (320 µM) of RM12 was found to have 15 or 20% of hemolytic activity; however, it was not significant with other tested concentrations (10, 20, 40, 80, and 160 µM). Further, the in vivo antioxidant properties of RM12 were experimented on zebrafish embryo, the intracellular ROS level was estimated by 5 mM H2O2 stress in the zebrafish embryo, and inhibition of apoptosis was evaluated. The antioxidant enzymes were extracted from the H2O2-stressed zebrafish embryo, and the intracellular ROS was eliminated due to RM12. Collectively, the experiment showed that the substance P from the freshwater murrel C. striatus possessed potent antioxidant properties; thus, it can further be focused to develop it as antioxidant molecule in aquaculture organisms.


Assuntos
Antioxidantes/farmacologia , Eritrócitos/efeitos dos fármacos , Peixes/metabolismo , Substância P/farmacologia , Animais , Compostos de Bifenilo/metabolismo , Catalase/metabolismo , Embrião não Mamífero/metabolismo , Eritrócitos/metabolismo , Feminino , Peixes/embriologia , Água Doce , Hemólise/efeitos dos fármacos , Radical Hidroxila/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Picratos/metabolismo , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo
7.
J Med Chem ; 64(11): 7778-7808, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34011153

RESUMO

The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains µ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D3 receptor (D3R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D3R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D3R. Structure-activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads (23, 28, and 40), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-D3R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.


Assuntos
Antagonistas de Dopamina/química , Ligantes , Receptores de Dopamina D3/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/uso terapêutico , Modelos Animais de Doenças , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/uso terapêutico , Desenho de Fármacos , Transferência Ressonante de Energia de Fluorescência , Camundongos , Simulação de Acoplamento Molecular , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Dor/tratamento farmacológico , Manejo da Dor , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Receptores Opioides mu/agonistas , Relação Estrutura-Atividade
8.
J Med Chem ; 64(11): 7453-7467, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34032427

RESUMO

There has been significant attention concerning the biased agonism of G protein-coupled receptors (GPCRs), and it has resulted in various pharmacological benefits. 5-HT7R belongs to a GPCR, and it is a promising pharmaceutical target for the treatment of neurodevelopmental and neuropsychiatric disorders. Based on our previous research, we synthesized a series of 6-chloro-2'-methoxy biphenyl derivatives 1, 2, and 3 with a variety of amine scaffolds. These compounds were evaluated for their binding affinities to 5-HTR subtypes and their functional selectivity toward the Gs protein and the ß-arrestin signaling pathways of 5-HT7R. Among them, 2-(6-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-N-ethylethan-1-amine, 2b, was found to be a G-protein-biased ligand of 5-HT7R. In an in vivo study with Shank3 transgenic mice, the self-grooming behavior test was performed with 2b, which increased the duration of self-grooming. The experiments further suggested that 5-HT7R is associated with autism spectrum disorders (ASDs) and could be a therapeutic target for the treatment of stereotypy in ASDs.


Assuntos
Compostos de Bifenilo/química , Ligantes , Receptores de Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microssomos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Serotonina/química , Relação Estrutura-Atividade
9.
Int J Biol Macromol ; 183: 927-935, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33971232

RESUMO

Human serum albumin (HSA) is widely used for the treatment of diverse clinical conditions to restore plasma volume, manage burns and treat hypoproteinemia.Although the HSA preparations should ideally preserve its functionality, the structural integrity and antioxidant properties of HSA may be compromised as a result of the manufacturing process. The present study examined seven commercially available HSA preparations for clinical use to investigate their post-translational modifications (PTMs) and antioxidant activity, including DPPH radical-scavenging, peroxyl radical antioxidant and metal binding activities, by means of mass spectrometry and Ellman's assay. The results confirmed that most of the PTMs of HSA and especially the oxidation of the free thiol residue varied between the different commercial albumins and the percentage of these PTMs were higher than those of physiological HSA. Moreover, HSA-DA isoform was increased at the end of the stability time and new oxidative modifications occurred in these samples. In conclusion, the bioprocesses for production of commercial albumins are responsible of their wide heterogeneity, being the ethanol fractionation and their storage conditions the more critical phases. Nonetheless, the Kedrion albumin shows a high content of free thiol and a lower concentration of PTMs than other commercial albumins.


Assuntos
Antioxidantes/metabolismo , Albumina Sérica Humana/metabolismo , Compostos de Bifenilo/metabolismo , Humanos , Oxirredução , Peróxidos/metabolismo , Picratos/metabolismo , Processamento de Proteína Pós-Traducional
10.
Eur J Med Chem ; 219: 113435, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33892272

RESUMO

The eukaryotic translation initiation factor 4E (eIF4E) is the master regulator of cap-dependent protein synthesis. Overexpression of eIF4E is implicated in diseases such as cancer, where dysregulation of oncogenic protein translation is frequently observed. eIF4E has been an attractive target for cancer treatment. Here we report a high-resolution X-ray crystal structure of eIF4E in complex with a novel inhibitor (i4EG-BiP) that targets an internal binding site, in contrast to the previously described inhibitor, 4EGI-1, which binds to the surface. We demonstrate that i4EG-BiP is able to displace the scaffold protein eIF4G and inhibit the proliferation of cancer cells. We provide insights into how i4EG-BiP is able to inhibit cap-dependent translation by increasing the eIF4E-4E-BP1 interaction while diminishing the interaction of eIF4E with eIF4G. Leveraging structural details, we designed proteolysis targeted chimeras (PROTACs) derived from 4EGI-1 and i4EG-BiP and characterized these on biochemical and cellular levels. We were able to design PROTACs capable of binding eIF4E and successfully engaging Cereblon, which targets proteins for proteolysis. However, these initial PROTACs did not successfully stimulate degradation of eIF4E, possibly due to competitive effects from 4E-BP1 binding. Our results highlight challenges of targeted proteasomal degradation of eIF4E that must be addressed by future efforts.


Assuntos
Compostos de Bifenilo/metabolismo , Fator de Iniciação 4E em Eucariotos/metabolismo , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4E em Eucariotos/genética , Humanos , Cinética , Simulação de Acoplamento Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Proteômica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação
11.
Acta Sci Pol Technol Aliment ; 20(2): 179-188, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33884855

RESUMO

BACKGROUND: The aim of the study was to evaluate the caffeine level and antioxidant activity of brews of specialty grade coffee compared to popular coffee brands. METHODS: Ten types of coffee were used, including 7 specialty Arabica, 1 Robusta and 2 popular cheap coffee brands. For caffeine determination, HPLC analysis and the spectrophotometric method were used as reference. The total polyphenol content and antioxidant capacity (DPPH and FRAP methods) were evaluated. For two selected high-quality coffees, the influence of the brewing method on the antioxidant activity and caffeine content in the brews was assayed. RESULTS: Regarding the caffeine content, differences between specialty coffee brews and popular products were not found, and an average level amounted to 56 and 40 mg/ml, respectively. In contrast, the antioxidant capacity of specialty coffee brews was significantly higher than for popular ones, independently of the test used. The highest scavenging ability and total phenolic content was found for S3 specialty coffee (46.15% of DPPH inhibition and 58.7 mg GAE/ml, respectively), whereas the lowest was found for popular coffee (about 35% of DPPH inhibition and about 41 mg/GAE/ml). For two selected high-quality coffees, the influence of the brewing method on the antioxidant activity and caffeine content in the brews was tested. It was found that the use of a dripper (overflow brewing method) provides the brew with the best antioxidant properties but with moderate caffeine levels. CONCLUSIONS: It was found that 'specialty' quality coffees do not differ from popular brands in terms of caffeine content, but significantly outweigh them in terms of antioxidant activity. This property can be beneficial in the case of a high consumption of coffee, due to antiradical protective effects without the risk of caffeine overdose.


Assuntos
Antioxidantes/farmacologia , Cafeína/análise , Café/química , Manipulação de Alimentos/métodos , Polifenóis/farmacologia , Antioxidantes/análise , Compostos de Bifenilo/metabolismo , Coffea/química , Café/classificação , Humanos , Picratos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/análise
12.
Acta Sci Pol Technol Aliment ; 20(2): 223-236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33884859

RESUMO

BACKGROUND: Economically important vegetables are a strong source of antioxidants with different characteristics. Capsicum L. (pepper) is an important agricultural plant because of its economical, medicinal, and nutritional values. METHODS: This study aimed to test antioxidant parameters in the fruits of 9 cultivars of Capsicum annuum L. (CA 01-09), 7 cultivars of C. baccatum L. (CB 01-07), and 11 cultivars of C. chinense Jacq. (CC 01-11). The antioxidant activity of the investigated Capsicum cultivars was measured, along with the free radical scavenging activity (FRSA), using the DPPH method, and the molybdenum reducing power (MRP) was expressed as mg TE (Trolox equivalent) per g of DW (dry weight). Total polyphenol content (TPC), expressed as mg GAE (gallic acid equivalent) per g of DW, total flavonoid content (TFC), expressed as mg QE (quercetin equivalent) per g of DW, and total phenolic acid content (TPAC), expressed as mg CAE (caffeic acid equivalent) per g of DW, were the basic antioxidant parameters of antioxidant activity in this study. RESULTS: All investigated Capsicum extracts exhibited FRSA from 1.45 (CC-06) to 8.21 (CC-05) mg TE/g and MRP from 24.84 (CA-06) to 198.21 (CB-07) mg TE/g. The TPC of the tested extracts ranged from 10.13 (CB-03) to 38.68 (CB-07) mg GAE/g. The TFC of the studied samples showed values from 5.73 (CB-03) to 27.32 (CB-07) mg QE/g and TPAC from 2.24 (CB-03) to 13.07 (CC-07) mg CAE/g. A very strong correlation was found in the investigated cultivars between TPC and TPAC (r = 0.932, 0.839 and 0.848, respectively), and between TPC and TFC (r = 0.921, 0.982 and 0.939, respectively). Very strong relations were also found between TPC and FRSA (r = 0.820) in the C. annuum cultivars and between TPC and MRP (r = 0.898) in the C. baccatum cultivars. CONCLUSIONS: This study found useful results concerning the antioxidant potential of the fruits of Capsicum cultivars. The data obtained demonstrate the strong antioxidant activity of cultivars of Capsicum, which can be used in the food industry because of the commercial importance of these fruits.


Assuntos
Antioxidantes/farmacologia , Capsicum/química , Flavonoides/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Antioxidantes/análise , Compostos de Bifenilo/metabolismo , Capsicum/classificação , Flavonoides/análise , Frutas/química , Humanos , Hidroxibenzoatos/análise , Hidroxibenzoatos/farmacologia , Fenóis/análise , Picratos/metabolismo , Extratos Vegetais/química , Polifenóis/análise , Polifenóis/farmacologia , Especificidade da Espécie , Verduras/química
13.
Acta Sci Pol Technol Aliment ; 20(2): 237-245, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33884860

RESUMO

BACKGROUND: In recent years, increasing health awareness in consumers has motivated breweries to expand their beverage ranges with products with increased biological value. The aim of the present research was to develop probiotic wort-based beverages with grapefruit or tangerine zest essential oil addition. METHODS: Wort was produced with 60% Pilsen malt, 20% Vienna malt and 20% Caramel Munich ІІ malt with and without the addition of 0.05% (v/v) grapefruit or tangerine essential oils. It was inoculated with the probiotic yeast strain Saccharomyces cerevisiae var. boulardii Y1. Fermentations were carried out at a constant temperature of 10°C for 5 days. The dynamics of the extract, the alcohol content and the concentration of viable cells were monitored daily. The total phenolic content, phenolic acid and flavonoid phenolic compounds were determined because of their antioxidant activity. The antioxidant activity was determined by radical scavenging assay (DPPH) and ferric reducing antioxidant power (FRAP). A descriptive organoleptic evaluation of the final beverages was performed. RESULTS: The essential oils inhibited yeast growth to some extent at the beginning of the fermentation, even at a concentration of 0.05% (v/v), which resulted in lower alcohol content in the beverages with essential oil addition. Nevertheless, at the end of fermentation the concentration of viable cells was almost equal in all the beverages. Tangerine essential oil addition led to the highest content of phenolics, of which phenolic acids predominated. Therefore, the highest antioxidant activity of the beverage with tangerine essential oil can be ascribed to phenolic acids. The results of the sensorial evaluation also showed that the panel had preference towards the beverage with tangerine essential oil. CONCLUSIONS: The combination of essential oil and the probiotic yeast strain resulted in beverages with higher biological value than the beverages produced with the probiotic strain alone. The results obtained will be used for optimisation of process variables in the production of pilot-scale wort-based probiotic beverages with essential oil addition.


Assuntos
Antioxidantes/farmacologia , Bebidas/microbiologia , Citrus/química , Fermentação , Manipulação de Alimentos/métodos , Óleos Voláteis/farmacologia , Probióticos , Antioxidantes/análise , Bebidas/análise , Compostos de Bifenilo/metabolismo , Citrus paradisi/química , Flavonoides/análise , Flavonoides/farmacologia , Microbiologia de Alimentos , Sucos de Frutas e Vegetais/análise , Sucos de Frutas e Vegetais/microbiologia , Humanos , Óleos Voláteis/química , Fenóis/análise , Fenóis/farmacologia , Picratos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Saccharomyces cerevisiae
14.
J Med Chem ; 64(9): 5447-5469, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33904752

RESUMO

The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-XL. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival.


Assuntos
Antineoplásicos/química , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ureia/análogos & derivados , Proteína bcl-X/antagonistas & inibidores , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Camundongos , Simulação de Dinâmica Molecular , Nitrofenóis/química , Nitrofenóis/metabolismo , Piperazinas/química , Piperazinas/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo , Ressonância de Plasmônio de Superfície , Ureia/metabolismo , Ureia/farmacologia , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
15.
J Med Chem ; 64(4): 2186-2204, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33570940

RESUMO

The zinc-containing histone deacetylase enzyme HDAC7 is emerging as an important regulator of immunometabolism and cancer. Here, we exploit a cavity in HDAC7, filled by Tyr303 in HDAC1, to derive new inhibitors. Phenacetyl hydroxamates and 2-phenylbenzoyl hydroxamates bind to Zn2+ and are 50-2700-fold more selective inhibitors of HDAC7 than HDAC1. Phenylbenzoyl hydroxamates are 30-70-fold more potent HDAC7 inhibitors than phenacetyl hydroxamates, which is attributed to the benzoyl aromatic group interacting with Phe679 and Phe738. Phthalimide capping groups, including a saccharin analogue, decrease rotational freedom and provide hydrogen bond acceptor carbonyl/sulfonamide oxygens that increase inhibitor potency, liver microsome stability, solubility, and cell activity. Despite being the most potent HDAC7 inhibitors to date, they are not selective among class IIa enzymes. These strategies may help to produce tools for interrogating HDAC7 biology related to its catalytic site.


Assuntos
Benzamidas/farmacologia , Benzenoacetamidas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Benzamidas/síntese química , Benzamidas/metabolismo , Benzenoacetamidas/síntese química , Benzenoacetamidas/metabolismo , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Células THP-1
16.
Platelets ; 32(1): 105-112, 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-32079453

RESUMO

Platelet lifespan is regulated by intrinsic apoptosis. Platelet apoptosis can be triggered by BH3 mimetics that inhibit the pro-survival Bcl-2 family protein, Bcl-xL. Here, we investigated several small molecules that are reported to act as BH3 mimetics and compared their effects to the well-established BH3 mimetic, ABT-737. Platelet phosphatidylserine (PS) exposure was determined by flow cytometry. Changes in cytosolic Ca2+ signaling were detected using Cal-520. Plasma membrane integrity was determined by calcein leakage. The roles of caspases and calpain in these processes were determined using Q-VD-OPh and calpeptin, respectively. As previously reported, ABT-737 triggered PS exposure in a caspase-dependent manner and calcein loss in a caspase and calpain-dependent manner. In contrast, AT-101 and sabutoclax triggered PS exposure independently of caspases. HA14-1 also triggered PS exposure in a caspase-independent but calpain-dependent manner. There were also significant differences in the pattern and protease-dependency of cytosolic Ca2+ signaling in response to these drugs compared to ABT-737. Since there are clear differences between the action of ABT-737 and the other putative BH3 mimetics investigated here, AT-101, HA14-1 and sabutoclax cannot be considered as acting as BH3 mimetics in platelets. Furthermore, the platelet death caused by these drugs is likely to be distinct from apoptosis.


Assuntos
Compostos de Bifenilo/metabolismo , Plaquetas/metabolismo , Nitrofenóis/metabolismo , Sulfonamidas/metabolismo , Animais , Apoptose , Voluntários Saudáveis , Humanos , Camundongos , Piperazinas/metabolismo
17.
J Sci Food Agric ; 101(6): 2210-2217, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33006387

RESUMO

BACKGROUND: Boscalid is often used to extend the storage time of postharvest cherry tomato. Pesticide residue has become an issue of food safety. This study sought to investigate the spatial distribution of boscalid residue in cherry tomato fruits and to determine the effect of 24-epibrassinolide (EBR) in promoting boscalid degradation. RESULTS: Boscalid could quickly penetrate into cherry tomatoes, but mainly remained in the peel. The migration of boscalid from the peel into the core was a time-consuming and complex process during storage. After 72 h, boscalid residues in the pulp and the core began to accumulate gradually. The exogenous application of EBR activated peroxidase, glutathione reductase and glutathione S-transferase, and effectively promoted the degradation of boscalid by a maximum decrease of 44.8% in peel, 54.0% in pulp and 71.2% in core. CONCLUSION: As one of the common pesticides, boscalid had a strong ability to enter the cherry tomato and thus become a potential risk for public consumption. Therefore, rational use of pesticides is recommended. The results of this study indicate that the possible risk of boscalid residue could be alleviated by EBR pretreatment through activating detoxification enzymes. © 2020 Society of Chemical Industry.


Assuntos
Compostos de Bifenilo/metabolismo , Brassinosteroides/farmacologia , Fungicidas Industriais/metabolismo , Lycopersicon esculentum/enzimologia , Niacinamida/análogos & derivados , Proteínas de Plantas/metabolismo , Esteroides Heterocíclicos/farmacologia , Compostos de Bifenilo/química , Ativação Enzimática/efeitos dos fármacos , Frutas/química , Frutas/efeitos dos fármacos , Frutas/enzimologia , Frutas/metabolismo , Fungicidas Industriais/química , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Lycopersicon esculentum/química , Lycopersicon esculentum/efeitos dos fármacos , Lycopersicon esculentum/metabolismo , Niacinamida/química , Niacinamida/metabolismo , Peroxidase/metabolismo , Resíduos de Praguicidas/química , Resíduos de Praguicidas/metabolismo
18.
FEBS J ; 288(13): 3962-3972, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33064873

RESUMO

Mesenchymal stromal cells (MSCs) are nonhematopoietic cells that have been clinically explored as investigational cellular therapeutics for tissue injury regeneration and immune-mediated diseases. Their pharmaceutical properties arise from activation of endogenous receptors and transcription factors leading to a paracrine effect which mirror the biology of progenitors from which they arise. The aryl hydrocarbon receptor (AhR) is a transcription factor that has been extensively studied as an environmental sensor for xenobiotics, but recent findings suggest it can modulate immunological functions. Both genetic and pharmacological investigations revealed that MSCs express AhR and that it plays roles in inflammation, immunomodulation, and mesodermal plasticity of endogenous MSCs. Further, AhR has been shown to interact with key signaling cascades associated with these conditions. Therefore, AhR has potential to be an attractive target in both endogenous and culture-adapted MSCs for novel therapeutics to treat inflammation and other age-related disorders.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Compostos de Bifenilo/metabolismo , Humanos , Ligantes , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Choque Séptico/genética , Choque Séptico/metabolismo , Fatores de Transcrição/genética
19.
Protein Expr Purif ; 177: 105748, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32911063

RESUMO

The antioxidant activity and cell viability of feather hydrolysates obtained with the Bacillus licheniformis were evaluated using an in-vitro model. The results indicate that feathers-derived peptides under 3 kDa have antioxidant activity with IC50 values of 5.03 ± 0.215 mg/mL by using DPPH antioxidant assay. Although the antioxidant activity of the peptides under 3 kDa preserved after applying diverse heating (from 20 to 100 °C), they lost their activity under strongly acidic or alkaline conditions. Antioxidant activity of the mixed feather bioactive peptides (MFBPs) obtained with partial purification of peptides under 3 kDa was with IC50 amount of 0.169 mg/mL ± 0.004 using DPPH radical scavenging assay. Also, MFBPs within an amount range of from 0.0048 to 5.0 mg/mL, illustrated no cytotoxicity to gingival fibroblast blood cell lines. In light of our results, the obtained value-added peptides could be useful in different food products as a future functional ingredient with antioxidant potency.


Assuntos
Antioxidantes/farmacologia , Bacillus licheniformis/química , Plumas/química , Queratinas/farmacologia , Peptídeos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Bacillus licheniformis/enzimologia , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Galinhas , Temperatura Alta , Humanos , Hidrólise , Queratinas/química , Queratinas/isolamento & purificação , Peso Molecular , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Peptídeos/química , Peptídeos/isolamento & purificação , Picratos/antagonistas & inibidores , Picratos/metabolismo
20.
Chembiochem ; 22(6): 985-987, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33205588

RESUMO

Chemical biologists use chemical tools to answer biological questions. The translational application of these principles has led to an explosion in the discovery and druggability of new protein targets, including protein-protein interactions (PPIs). Proteins tend to interact with other macromolecules using relatively large and featureless binding surfaces, which has hampered traditional drug discovery efforts, particularly for interactions with weaker affinity. In this article, I discuss several emerging strategies for targeting PPIs, including computational and structural methods and novel screening approaches. In particular, I focus on hijacking intrinsic protein allosteric pathways for the discovery and design of small-molecule and peptide ligands.


Assuntos
Mapas de Interação de Proteínas , Proteínas/metabolismo , Regulação Alostérica , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Descoberta de Drogas , Ligantes , Nitrofenóis/química , Nitrofenóis/metabolismo , Nitrofenóis/farmacologia , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Ligação Proteica , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas/química , Proteínas Proto-Oncogênicas c-bcl-2/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Proteína bcl-X/química , Proteína bcl-X/metabolismo
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