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1.
Biosensors (Basel) ; 11(9)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34562912

RESUMO

An amperometric biosensor based on tyrosinase, immobilized onto a carbon black paste electrode using glutaraldehyde and BSA was constructed to detect competitive inhibitors. Three inhibitors were used in this study: benzoic acid, sodium azide, and kojic acid, and the obtained values for fifty percent of inhibition (IC50) were 119 µM, 1480 µM, and 30 µM, respectively. The type of inhibition can also be determined from the curve of the degree of inhibition by considering the shift of the inhibition curves. Amperometric experiments were performed with a biosensor polarized at the potential -0.15 V vs. Ag/AgCl and using 0.1 M phosphate buffer (pH 6.8) as an electrolyte. Under optimized conditions, the proposed biosensor showed a linear amperometric response toward catechol detection from 0.5 µM to 38 µM with a detection limit of 0.35 µM (S/N = 3), and its sensitivity was 66.5 mA M-1 cm-2. Moreover, the biosensor exhibited a good storage stability. Conversely, a novel graphical plot for the determination of reversible competitive inhibition was represented for free tyrosinase. The graph consisted of plotting the half-time reaction (t1/2) as a function of the inhibitor concentration at various substrate concentrations. This innovative method relevance was demonstrated in the case of kojic acid using a colorimetric bioassay relying on tyrosinase inhibition. The results showed that the t1/2 provides an extended linear range of tyrosinase inhibitors.


Assuntos
Técnicas Biossensoriais , Monofenol Mono-Oxigenase/análise , Catecóis , Eletroquímica , Eletrodos , Inibidores Enzimáticos/análise , Enzimas Imobilizadas , Concentração de Íons de Hidrogênio , Cinética , Monofenol Mono-Oxigenase/antagonistas & inibidores
2.
An Acad Bras Cienc ; 93(suppl 3): e20191341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34378634

RESUMO

In this study, we aimed to exploit natural extracts from the spicy vegetables, which are rich in phenolic compounds as an initial treatment step in the cold storage process for shrimp. Firstly, 40 extracts from 10 types of spicy vegetables in Vietnam were prepared and tested for their bioactivities. Among samples, the extract from Persicaria Odorata leaves (E-4) exhibited the highest potential of scavenging DPPH free radical (IC50 of 7.54 µg.mL-1) and decreasing tyrosinase activity with the inhibition percentage of 54.2 % at the concentration of 100 mg/mL. Twenty-two out of a total of 36 chemical compounds in the E-4 extract identified using HPLC-MS technique were phenolic compounds, in which four compounds (morin, quercetin, fisetin, astragalin) are flavonoids. Shrimp (Litopenaus vannamei) samples were treated with the E-4 extract having lower gray values, lipid peroxidation values, and microbiological counts than those of the control samples after 7 days of storage at 2 oC. These results show the potential of using the natural extract as a safe and effective alternative for commercial chemical-derived preservatives in the shrimp storage process.


Assuntos
Antioxidantes , Conservação de Alimentos , Monofenol Mono-Oxigenase , Penaeidae , Extratos Vegetais/química , Animais , Antioxidantes/química , Flavonoides , Monofenol Mono-Oxigenase/antagonistas & inibidores , Folhas de Planta/química , Polygonaceae/química , Verduras , Vietnã
3.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360580

RESUMO

Melanin causes melasma, freckles, age spots, and chloasma. Anti-melanogenic agents can prevent disease-related hyperpigmentation. In the present study, the dose-dependent tyrosinase inhibitory activity of Avenanthramide (Avn)-A-B-C was demonstrated, and 100 µM Avn-A-B-C produced the strongest competitive inhibition against inter-cellular tyrosinase and melanin synthesis. Avn-A-B-C inhibits the expression of melanogenesis-related proteins, such as TRP1 and 2. Molecular docking simulation revealed that AvnC (-7.6 kcal/mol) had a higher binding affinity for tyrosinase than AvnA (-7.3 kcal/mol) and AvnB (-6.8 kcal/mol). AvnC was predicted to interact with tyrosinase through two hydrogen bonds at Ser360 (distance: 2.7 Å) and Asn364 (distance: 2.6 Å). In addition, AvnB and AvnC were predicted to be skin non-sensitizers in mammals by the Derek Nexus Quantitative Structure-Activity Relationship system.


Assuntos
Simulação por Computador , Melaninas/biossíntese , Melanoma/tratamento farmacológico , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pele/efeitos dos fármacos , alfa-MSH/farmacologia , ortoaminobenzoatos/farmacologia , Hormônios/farmacologia , Humanos , Técnicas In Vitro , Melanoma/metabolismo , Melanoma/patologia , Simulação de Acoplamento Molecular , Células Tumorais Cultivadas
4.
Molecules ; 26(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34443550

RESUMO

To confirm that the ß-phenyl-α,ß-unsaturated thiocarbonyl (PUSTC) scaffold, similar to the ß-phenyl-α,ß-unsaturated carbonyl (PUSC) scaffold, acts as a core inhibitory structure for tyrosinase, twelve (Z)-5-(substituted benzylidene)-4-thioxothiazolidin-2-one ((Z)-BTTZ) derivatives were designed and synthesized. Seven of the twelve derivatives showed stronger inhibitory activity than kojic acid against mushroom tyrosinase. Compound 2b (IC50 = 0.47 ± 0.97 µM) exerted a 141-fold higher inhibitory potency than kojic acid. Kinetic studies' results confirmed that compounds 2b and 2f are competitive tyrosinase inhibitors, which was supported by high binding affinities with the active site of tyrosinase by docking simulation. Docking results using a human tyrosinase homology model indicated that 2b and 2f might potently inhibit human tyrosinase. In vitro assays of 2b and 2f were conducted using B16F10 melanoma cells. Compounds 2b and 2f significantly and concentration-dependently inhibited intracellular melanin contents, and the anti-melanogenic effects of 2b at 10 µM and 2f at 25 µM were considerably greater than the inhibitory effect of kojic acid at 25 µM. Compounds 2b and 2f similarly inhibited cellular tyrosinase activity and melanin contents, indicating that the anti-melanogenic effects of both were due to tyrosinase inhibition. A strong binding affinity with the active site of tyrosinase and potent inhibitions of mushroom tyrosinase, cellular tyrosinase activity, and melanin generation in B16F10 cells indicates the PUSTC scaffold offers an attractive platform for the development of novel tyrosinase inhibitors.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Melaninas/biossíntese , Tiazóis/química , Tiazóis/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Inibidores Enzimáticos/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/metabolismo , Conformação Proteica , Relação Estrutura-Atividade , Tiazóis/metabolismo
5.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361729

RESUMO

Tyrosinase (TYR) is a type III copper oxidase present in fungi, plants and animals. The inhibitor of human TYR plays a vital role in pharmaceutical and cosmetic fields by preventing synthesis of melanin in the skin. To search for an effective TYR inhibitor from various plant extracts, a kinetic study of TYR inhibition was performed with mushroom TYR. Among Panax ginseng, Alpinia galanga, Vitis vinifera and Moringa oleifera, the extracts of V. vinifera seed, A. galanga rhizome and M. oleifera leaf reversibly inhibited TYR diphenolase activity with IC50 values of 94.8 ± 0.2 µg/mL, 105.4 ± 0.2 µg/mL and 121.3 ± 0.4 µg/mL, respectively. Under the same conditions, the IC50 values of the representative TYR inhibitors of ascorbic acid and kojic acid were found at 235.7 ± 1.0 and 192.3 ± 0.4 µg/mL, respectively. An inhibition kinetics study demonstrated mixed-type inhibition of TYR diphenolase by A. galanga and V. vinifera, whereas a rare uncompetitive inhibition pattern was found from M. oleifera with an inhibition constant of Kii 73 µg/mL. Phytochemical investigation by HPLC-MS proposed luteolin as a specific TYR diphenolase ES complex inhibitor, which was confirmed by the inhibition kinetics of luteolin. The results clearly showed that studying TYR inhibition kinetics with plant extract mixtures can be utilized for the screening of specific TYR inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Luteolina/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Moringa oleifera/química , Agaricales/química , Agaricales/enzimologia , Alpinia/química , Ácido Ascórbico/química , Ácido Ascórbico/isolamento & purificação , Ácido Ascórbico/farmacologia , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Proteínas Fúngicas/isolamento & purificação , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Cinética , Luteolina/química , Luteolina/isolamento & purificação , Monofenol Mono-Oxigenase/isolamento & purificação , Panax/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Pironas/química , Pironas/isolamento & purificação , Pironas/farmacologia , Rizoma/química , Sementes/química , Vitis/química
6.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201208

RESUMO

Tyrosinase is the central enzyme involved in the highly complex process of melanin formation, catalyzing the rate-limiting steps of this biosynthetic pathway. Due to such a preponderant role, it has become a major target in the treatment of undesired skin pigmentation conditions and also in the prevention of enzymatic food browning. Numerous phenolic-based structures from natural sources have been pointed out as potential tyrosinase inhibitors, including anthocyanins. The aim of the present study was to individually assess the tyrosinase inhibitory activity of eight purified compounds with a variable degree of structural complexity: native anthocyanins, deoxyanthocyanins, and pyranoanthocyanins. The latter two, the groups of anthocyanin-related compounds with enhanced stability, were tested for the first time. Compounds 1 to 4 (luteolinidin, deoxymalvidin, cyanidin-, and malvidin-3-O-glucoside) revealed to be the most effective inhibitors, and further kinetic studies suggested their inhibition mechanism to be of a competitive nature. Structure-activity relationships were proposed based on molecular docking studies conducted with mushroom tyrosinase (mTYR) and human tyrosinase-related protein 1 (hTYRP1) crystal structures, providing information about the binding affinity and the different types of interactions established with the enzyme's active center which corroborated the findings of the inhibition and kinetic studies. Overall, these results support the applicability of these compounds as pigmentation modulators.


Assuntos
Antocianinas/química , Antocianinas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Agaricales/enzimologia , Catálise , Simulação por Computador , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxirredução , Relação Estrutura-Atividade
7.
Molecules ; 26(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206838

RESUMO

Polyphenols, widely distributed in the genus Melastoma plants, possess extensive cellular protective effects such as anti-inflammatory, anti-tyrosinase, and anti-obesity, which makes it a potential anti-inflammatory drug or enzyme inhibitor. Therefore, the aim of this study is to screen for the anti-inflammatory and enzyme inhibitory activities of compounds from title plant. Using silica gel, MCI, ODS C18, and Sephadex LH-20 column chromatography, as well as semipreparative HPLC, the extract of Melastoma normale roots was separated. Four new ellagitannins, Whiskey tannin C (1), 1-O-(4-methoxygalloyl)-6-O-galloyl-2,3-O-(S)-hexahydroxydiphenoyl-ß-d-glucose (2), 1-O-galloyl-6-O-(3-methoxygalloyl)-2,3-O-(S)-hexahydroxydiphenoyl-ß-d-glucose (3), and 1-O-galloyl-6-O-vanilloyl-2,3-O-(S)-hexahydroxydiphenoyl-ß-d-glucose (4), along with eight known polyphenols were firstly obtained from this plant. The structures of all isolates were elucidated by HRMS, NMR, and CD analyses. Using lipopolysaccharide (LPS)-stimulated RAW2 64.7 cells, we investigated the anti-inflammatory activities of compounds 1-4, unfortunately, none of them exhibit inhibit nitric oxide (NO) production, their IC50 values are all > 50 µM. Anti-tyrosinase activity assays was done by tyrosinase inhibition activity screening model. Compound 1 showed weak tyrosinase inhibitory activity with IC50 values of 426.02 ± 11.31 µM. Compounds 2-4 displayed moderate tyrosinase inhibitory activities with IC50 values in the range of 124.74 ± 3.12-241.41 ± 6.23 µM. The structure-activity relationships indicate that hydroxylation at C-3', C-4', and C-3 in the flavones were key to their anti-tyrosinase activities. The successful isolation and structure identification of ellagitannin provide materials for the screening of anti-inflammatory drugs and enzyme inhibitors, and also contribute to the development and utilization of M. normale.


Assuntos
Anti-Inflamatórios/análise , Inibidores Enzimáticos/farmacologia , Taninos Hidrolisáveis/análise , Melastomataceae/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Extratos Vegetais/química , Polifenóis/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Extratos Vegetais/análise , Polifenóis/química , Células RAW 264.7
8.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208619

RESUMO

Skin pigment disorders are common cosmetic and medical problems. Many known compounds inhibit the key melanin-producing enzyme, tyrosinase, but their use is limited due to side effects. Natural-derived peptides also display tyrosinase inhibition. Abalone is a good source of peptides, and the abalone proteins have been used widely in pharmaceutical and cosmetic products, but not for melanin inhibition. This study aimed to predict putative tyrosinase inhibitory peptides (TIPs) from abalone, Haliotis diversicolor, using k-nearest neighbor (kNN) and random forest (RF) algorithms. The kNN and RF predictors were trained and tested against 133 peptides with known anti-tyrosinase properties with 97% and 99% accuracy. The kNN predictor suggested 1075 putative TIPs and six TIPs from the RF predictor. Two helical peptides were predicted by both methods and showed possible interaction with the predicted structure of mushroom tyrosinase, similar to those of the known TIPs. These two peptides had arginine and aromatic amino acids, which were common to the known TIPs, suggesting non-competitive inhibition on the tyrosinase. Therefore, the first version of the TIP predictors could suggest a reasonable number of the TIP candidates for further experiments. More experimental data will be important for improving the performance of these predictors, and they can be extended to discover more TIPs from other organisms. The confirmation of TIPs in abalone will be a new commercial opportunity for abalone farmers and industry.


Assuntos
Gastrópodes/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Algoritmos , Animais , Análise por Conglomerados , Biologia Computacional/métodos , Gastrópodes/química , Aprendizado de Máquina , Monofenol Mono-Oxigenase/farmacologia , Peptídeos/farmacologia
9.
Molecules ; 26(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34279385

RESUMO

This work aimed to evaluate the phenolic content and in vitro antioxidant, antimicrobial and enzyme inhibitory activities of the methanol extracts and their fractions of two edible halophytic Limonium species, L. effusum (LE) and L. sinuatum (LS). The total phenolic content resulted about two-fold higher in the ethyl acetate fraction of LE (522.82 ± 5.67 mg GAE/g extract) than in that of LS (274.87 ± 1.87 mg GAE/g extract). LC-MS/MS analysis indicated that tannic acid was the most abundant phenolic acid in both species (71,439.56 ± 3643.3 µg/g extract in LE and 105,453.5 ± 5328.1 µg/g extract in LS), whereas hyperoside was the most abundant flavonoid (14,006.90 ± 686.1 µg/g extract in LE and 1708.51 ± 83.6 µg/g extract in LS). The antioxidant capacity was evaluated by DPPH and TAC assays, and the stronger antioxidant activity in ethyl acetate fractions was highlighted. Both species were more active against Gram-positive bacteria than Gram negatives and showed considerable growth inhibitions against tested fungi. Interestingly, selective acetylcholinesterase (AChE) activity was observed with LE and LS. Particularly, the water fraction of LS strongly inhibited AChE (IC50 = 0.199 ± 0.009 µg/mL). The ethyl acetate fractions of LE and LS, as well as the n-hexane fraction of LE, exhibited significant antityrosinase activity (IC50 = 245.56 ± 3.6, 295.18 ± 10.57 and 148.27 ± 3.33 µg/mL, respectively). The ethyl acetate fraction and methanol extract of LS also significantly inhibited pancreatic lipase (IC50 = 83.76 ± 4.19 and 162.2 ± 7.29 µg/mL, respectively). Taken together, these findings warrant further investigations to assess the potential of LE and LS as a bioactive source that can be exploited in pharmaceutical, cosmetics and food industries.


Assuntos
Compostos Fitoquímicos/química , Extratos Vegetais/química , Plumbaginaceae/química , Polifenóis/análise , Acetilcolinesterase/metabolismo , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Proteínas de Peixes/antagonistas & inibidores , Proteínas de Peixes/metabolismo , Lipase/antagonistas & inibidores , Monofenol Mono-Oxigenase/antagonistas & inibidores , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia
10.
Molecules ; 26(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067030

RESUMO

Valonea tannin is a natural product readily extracted from acorn shells that has been suggested to have potential skin whitening properties. This study investigated the tyrosinase inhibition activity of extracted valonea tannin and the associated structure-function activity. Nuclear magnetic resonance spectroscopy and molecular weight analysis with gel permeation chromatography revealed that valonea tannin could be characterized as a hydrolysable tannin with galloyl, hexahydroxydiphenoyl and open formed-glucose moieties and an average molecular weight of 3042 ± 15 Da. Tyrosinase inhibition assays demonstrated that valonea tannin was 334 times more effective than gallic acid and 3.4 times more effective than tannic acid, which may relate to the larger molecular size. Kinetic studies of the inhibition reactions indicated that valonea tannin provided tyrosinase inhibition through mixed competitive-uncompetitive way. Stern-Volmer fitted fluorescence quenching analysis, isothermal titration calorimetry analysis and in silico molecule docking showed valonea tannin non-selectively bound to the surface of tyrosinase via hydrogen bonds and hydrophobic interactions. Inductively coupled plasma-optical emission spectroscopy and free radical scavenging assays indicated the valonea tannin had copper ion chelating and antioxidant ability, which may also contribute to inhibition activity. These results demonstrated the structure-function activity of valonea tannin as a highly effective natural tyrosinase inhibitor that may have commercial application in dermatological medicines or cosmetic products.


Assuntos
Inibidores Enzimáticos/farmacologia , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Antioxidantes/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Quelantes/farmacologia , Cobre/isolamento & purificação , Ácido Gálico/farmacologia , Cinética , Ligantes , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/metabolismo , Espectrometria de Fluorescência , Taninos/farmacologia , Termodinâmica
11.
Molecules ; 26(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066283

RESUMO

Tyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates L-DOPA and L-tyrosine. The dysregulation of tyrosinase is involved in skin cancer initiation. In the present study, using molecular modeling tools, we analyzed the inhibition activity of tyrosinase activity using kojic acid (KA) derivatives designed from aromatic aldehydes and malononitrile. All derivatives showed conformational affinity to the enzyme active site, and a favorable distance to chelate the copper ion, which is essential for enzyme function. Molecular dynamics simulations revealed that the derivatives formed promising complexes, presenting stable conformations with deviations between 0.2 and 0.35 Å. In addition, the investigated KA derivatives showed favorable binding free energies. The most stable KA derivatives showed the following binding free energies: -17.65 kcal mol-1 (D6), -18.07 kcal mol-1 (D2), -18.13 (D5) kcal mol-1, and -10.31 kcal mol-1 (D4). Our results suggest that these derivatives could be potent competitive inhibitors of the natural substrates of L-DOPA (-12.84 kcal mol-1) and L-tyrosine (-9.04 kcal mol-1) in melanogenesis.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Pironas/química , Pironas/farmacologia , Domínio Catalítico , Humanos , Levodopa/metabolismo , Melaninas/biossíntese , Melanócitos/metabolismo , Melanoma/metabolismo , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Neoplasias Cutâneas/metabolismo , Relação Estrutura-Atividade , Tirosina/metabolismo
12.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070680

RESUMO

We previously reported (E)-ß-phenyl-α,ß-unsaturated carbonyl scaffold ((E)-PUSC) played an important role in showing high tyrosinase inhibitory activity and that derivatives with a 4-substituted resorcinol moiety as the ß-phenyl group of the scaffold resulted in the greatest tyrosinase inhibitory activity. To examine whether the 4-substituted resorcinol moiety could impart tyrosinase inhibitory activity in the absence of the α,ß-unsaturated carbonyl moiety of the (E)-PUSC scaffold, 10 urolithin derivatives were synthesized. To obtain more candidate samples, the lactone ring in synthesized urolithins was reduced to produce nine reduced urolithins. Compounds 1c (IC50 = 18.09 ± 0.25 µM), 1h (IC50 = 4.14 ± 0.10 µM), and 2a (IC50 = 15.69 ± 0.40 µM) had greater mushroom tyrosinase-inhibitory activities than kojic acid (KA) (IC50 = 48.62 ± 3.38 µM). The SAR results suggest that the 4-substituted resorcinol motif makes an important contribution to tyrosinase inhibition. To investigate whether these compounds bind to human tyrosinase, a human tyrosinase homology model was developed. Docking simulations with mushroom and human tyrosinases showed that 1c, 1h, and 2a bind to the active site of both tyrosinases with higher binding affinities than KA. Pharmacophore analyses showed that two hydroxyl groups of the 4-substituted resorcinol entity act as hydrogen bond donors in both mushroom and human tyrosinases. Kinetic analyses indicated that these compounds were all competitive inhibitors. Compound 2a inhibited cellular tyrosinase activity and melanogenesis in α-MSH plus IBMX-stimulated B16F10 melanoma cells more strongly than KA. These results suggest that 2a is a promising candidate for the treatment of skin pigment disorders, and show the 4-substituted resorcinol entity importantly contributes to tyrosinase inhibition.


Assuntos
Agaricales/enzimologia , Cumarínicos , Inibidores Enzimáticos , Proteínas Fúngicas , Melanoma/enzimologia , Monofenol Mono-Oxigenase , Proteínas de Neoplasias/antagonistas & inibidores , Resorcinóis , Animais , Linhagem Celular Tumoral , Cumarínicos/química , Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/metabolismo , Humanos , Melaninas/biossíntese , Camundongos , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Proteínas de Neoplasias/metabolismo , Resorcinóis/química , Resorcinóis/farmacologia
13.
J Enzyme Inhib Med Chem ; 36(1): 1145-1164, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34074198

RESUMO

We report herein anti-proliferation effects of 4-arylthiosemicarbazides, with a cyclopentane substitution at N1 position, on highly virulent RH strain of Toxoplasma gondii. Among them, the highest in vitro anti-Toxoplasma activity was found with the meta-iodo derivative. Further experiments demonstrated inhibitory effects of thiosemicarbazides on tyrosinase (Tyr) activity, and good correlation was found between percentage of Tyr inhibition and IC50Tg. To confirm the concept that thiosemicarbazides are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites, the most potent Tyr inhibitors were tested for their efficacy of T. gondii growth inhibition. All of them significantly reduced the number of tachyzoites in the parasitophorous vacuoles (PVs) compared to untreated cells, as well as inhibited tachyzoites growth by impeding cell division. Collectively, these results indicate that compounds with the thiosemicarbazide scaffold are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites by deregulation of their crucial enzyme tyrosine hydroxylase (TyrH).


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Semicarbazidas/farmacologia , Toxoplasma/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Testes de Sensibilidade Parasitária , Semicarbazidas/síntese química , Semicarbazidas/química , Relação Estrutura-Atividade , Toxoplasma/crescimento & desenvolvimento
14.
Chem Biodivers ; 18(8): e2100299, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34086421

RESUMO

The article reports the chemical composition, antioxidant, six key enzymes inhibitory and antimicrobial activities of two solvent extracts (water and methanol) of leaves and stem bark of Uapaca togoensis. For chemical composition, methanol extract of stem bark exhibited significant higher total phenolic (129.86 mg GAE/g) and flavanol (10.44 mg CE/g) contents. Methanol extract of leaves and water extract of stem bark showed high flavonoids (20.94 mg RE/g) and phenolic acid (90.40 mg CAE/g) content, respectively. In addition, HPLC-ESI-TOF-MS analysis revealed that U. togoensis was rich in procyanidins. The methanol and water extracts of stem bark had overall superior antioxidant activity; however, only methanol extract of stem bark showed higher inhibition of cholinesterase (AChE: 2.57 mg GALAE/g; BChE: 4.69 mg GALAE/g), tyrosinase (69.53 mg KAE/g) and elastase (2.73 mmol CE/g). Potent metal chelating ability was showed by water extract of leaves (18.94 mg EDTAE/g), higher inhibition of amylase was detected for water extracts of leaves (0.94 mmol ACAE/g) and stem bark (0.92 mmol ACAE/g). The tested extracts have shown wide-spectrum antibacterial properties and these effects have shown to be more effective against Aspergillus ochraceus, Penicillium funiculosum, Trichoderma viride, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa. The results revealed that the antioxidant, enzyme inhibitory and antimicrobial activities depended on the extraction solvents and the parts of plant. Bioinformatics analysis on the 17 major compounds showed modulation of pathway associated with cancer. In brief, U. togoensis might be valuable as potential source of natural agents for therapeutic application.


Assuntos
Biflavonoides/química , Catequina/química , Biologia Computacional/métodos , Inibidores Enzimáticos/química , Magnoliopsida/química , Extratos Vegetais/química , Proantocianidinas/química , Amilases/antagonistas & inibidores , Amilases/metabolismo , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antioxidantes/química , Biflavonoides/isolamento & purificação , Biflavonoides/metabolismo , Biflavonoides/farmacologia , Catequina/isolamento & purificação , Catequina/metabolismo , Catequina/farmacologia , Cromatografia Líquida de Alta Pressão , Análise por Conglomerados , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Magnoliopsida/metabolismo , Testes de Sensibilidade Microbiana , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Casca de Planta/química , Casca de Planta/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Proantocianidinas/isolamento & purificação , Proantocianidinas/metabolismo , Proantocianidinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray
15.
Chem Biodivers ; 18(8): e2100207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34096170

RESUMO

Gundelia species are known as "Kenger-kereng dikeni" in Anatolia, and their aerial parts are consumed as food. Also, roots and seeds (disseminules) of the Gundelia species are used to prepare gum and coffee. The chemical contents of ethanol and hexane extracts of disseminules of 17 Gundelia species, 13 of them are endemic, were studied using LC/MS/MS and GC/MS. Additionally, their antioxidant potential and enzyme inhibitory capacity against acetyl- and butyryl-cholinesterase, urease, and tyrosinase were determined. The unsaturated fatty acid ratios of Gundelia species were higher than their saturated fatty acid ratio. The highest sum of oleic and linoleic acid was detected in G. tournefortii var. tenuisecta (70.42 %). ß-Sitosterol, α-amyrin, 3-acetyllupeol were identified in 17 Gundelia species by GC/MS, while chlorogenic acid and luteolin by LC/MS/MS as major compounds. The ethanol and hexane extracts of G. siirtica, G. rosea, and G. mesopotamica indicated good cholinesterase inhibitory activity. Among all species, ethanol extract of G. colemerikensis exhibited the best activity in ABTS (IC50 : 32.30±0.98 µg/mL), DPPH (IC50 : 59.91±0.89 µg/mL), and CUPRAC (A0.5 : 57.41±1.03 µg/mL) assays. Ethanol extract of G. colemerikensis also displayed the highest inhibitory activity against butyrylcholinesterase (51.14±0.25 % at 200 µg/mL), urease (51.71±1.75 % at 200 µg/mL), and tyrosinase (39.50±0.85 % at 200 µg/mL) enzymes. According to the chemometric analysis of fatty acids, four groups were observed. Therefore, it is suggested that G. colemerikensis can be used in the pharmaceutical, food, and cosmetic industries due to its antioxidant and enzyme inhibition properties.


Assuntos
Asteraceae/química , Inibidores Enzimáticos/química , Compostos Fitoquímicos/química , Extratos Vegetais/química , Antioxidantes/química , Asteraceae/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Ácidos Graxos/química , Ácidos Graxos/isolamento & purificação , Frutas/química , Frutas/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/metabolismo , Análise de Componente Principal , Sementes/química , Sementes/metabolismo , Espectrometria de Massas em Tandem , Urease/antagonistas & inibidores , Urease/metabolismo
16.
Chem Biodivers ; 18(8): e2100316, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34114723

RESUMO

The genus Rhanterium (Asteraceae) is a widely distributed medicinal plant throughout western North Africa and some Rhanterium species are used in folk medicine. The aim of research was to investigate methanolic extracts from different parts (flowers, leaves, and stems) of Tunisian Rhanterium suaveolens as potential sources of bioactive products useful for healthy purposes. In particular, were analyzed the phenolic composition of these extracts and their antioxidant, anti-inflammatory, and anti-tyrosinase properties. The phytochemical analyses were performed using standard colorimetric procedures, HPLC-DAD and HPLC-DAD-ESI-MS. Then, several in vitro cell-free assays have been used to estimate the antioxidant/free radical scavenging capability of the extracts. Moreover, in vitro, and in vivo anti-melanogenesis activities of these extracts were tested, respectively, with the tyrosinase inhibition assay and the Zebrafish embryo model. Finally, the anti-inflammatory potential of these extracts in an in vitro model of acute intestinal inflammation in differentiated Caco-2 cells was evaluated. The R. suaveolens extracts under study appeared particularly rich in flavonols and hydroxycinnamic acids and all extracts appeared endowed with good antioxidant/free radical scavenging properties, being the flower extracts slightly more active than the others. Moreover, R. suaveolens flowers extract was able to inhibit in vitro tyrosinase activity and exhibited bleaching effects on the pigmentation of zebrafish embryos. Furthermore, all extracts showed good anti-inflammatory activity in intestinal epithelial cells as demonstrated by the inhibition of TNF-α-induced gene expression of IL-6 and IL-8. R. suaveolens aerial parts may be considered as a potential source of whitening agents, as well as of agents for the treatment of disorders related to oxidative stress and inflammation.


Assuntos
Anti-Inflamatórios/química , Asteraceae/química , Inibidores Enzimáticos/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Extratos Vegetais/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Asteraceae/metabolismo , Células CACO-2 , Diferenciação Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Ácidos Cumáricos/química , Ácidos Cumáricos/isolamento & purificação , Ácidos Cumáricos/metabolismo , Ácidos Cumáricos/farmacologia , Embrião não Mamífero/citologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Flavonóis/química , Flavonóis/isolamento & purificação , Flavonóis/metabolismo , Flavonóis/farmacologia , Humanos , Melaninas/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Tunísia , Peixe-Zebra/metabolismo
17.
J Biosci Bioeng ; 132(1): 9-17, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33934979

RESUMO

Rice is a source of bioactive compounds related to human health and has been used for both consumption and traditional medicine. The authors investigated the synergistic and additive effect of rice extract (RE) combined with five aromatic compounds against three enzymes: α-glucosidase, α-amylase and tyrosinase. RE was purified by thin-layer chromatography (TLC) and preparative TLC (PTLC) with different solvent systems. RE had higher α-glucosidase and α-amylase inhibitory activity than the five aromatic compounds, while the five aromatic compounds had higher tyrosinase inhibitory activity than RE. The combination of RE/acarbose produced synergic inhibition of α-glucosidase and α-amylase, whereas RE showed additive inhibition of both enzymes when combined with aromatic compounds. The five aromatic compounds showed additive inhibition of tyrosinase when combined with RE. The combination of 2-methoxy-4-vinylphenol/vanillin/guaiacol produced synergistic inhibition of α-amylase while showing antagonism of α-glucosidase and tyrosinase. Interestingly, the RE produced additive inhibition of α-glucosidase, α-amylase and tyrosinase when combined with the 2-methoxy-4-vinylphenol/vanillin/guaiacol combination. RE had rich bioactive compounds related to α-glucosidase, α-amylase and tyrosinase inhibitory activity. Volatile compounds, including 2-methoxy-4-vinylphenol, vanillin and guaiacol, enhanced the inhibitory activity of RE against α-glucosidase, α-amylase and tyrosinase activities.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Hidrocarbonetos Aromáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oryza/química , Extratos Vegetais/farmacologia , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/metabolismo , Interações Medicamentosas , Humanos
18.
Chem Biodivers ; 18(7): e2100245, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33989453

RESUMO

The aim of this research was to investigate and compare the antioxidant, anti-tyrosinase, anti-aging, and anti-inflammatory activities of 16 herbal extracts for topical application in cosmetic/cosmeceutical products. Herbal plant materials were extracted by infusion in boiled water for 15 min. The total phenolic content and total flavonoid content of each extract were investigated by the Folin-Ciocalteu and aluminum chloride methods, respectively. Antioxidant activities were investigated using 2,2'-diphenyl-1-picrylhydrazyl and a ferric reducing antioxidant power assay. Anti-tyrosinase and anti-aging activities were investigated using an in vitro enzymatic-spectrophotometric method. Anti-inflammatory activities were investigated using an enzyme-linked immunosorbent assay. The findings show that the Stevia rebaudiana extract has the most significant levels of both phenols and flavonoids (p<0.05). The S. rebaudiana, Rosa damascene, and Phyllanthus emblica extracts possessed the most significant antioxidant activities (p<0.05) and a promising whitening effect with moderate anti-tyrosinase activities. Furthermore, the Echinacea purpurea extract possessed the most significant anti-collagenase (78.5±0.0 %), anti-elastase (69.0±1.4 %), and anti-hyaluronidase activity (64.2±0.3 %). The Morus alba extract possessed the most significant anti-inflammatory activity since it could inhibit the secretion of interleukin-6 and tumor necrosis factor-α (p<0.05). Therefore, these herbal extracts have promising skin benefits and have potential for use as active ingredients in cosmetic/cosmeceutical products.


Assuntos
Envelhecimento/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Extratos Vegetais/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Echinacea/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Monofenol Mono-Oxigenase/metabolismo , Phyllanthus emblica/química , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Rosa/química , Pele/efeitos dos fármacos , Stevia/química
19.
Food Funct ; 12(9): 3978-3991, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977989

RESUMO

Tyrosinase is considered a molecular marker of melanoma, and few natural antitumor drugs targeting tyrosinase have been identified. In this study, proanthocyanidins (PAs) were isolated from the leaves of Photinia × fraseri and their structures were characterized by high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and the effects of antityrosinase activity were investigated. The results showed that the basic structural units of PAs are composed of catechin and epicatechin and that oligomer is the main component. PAs exhibited better antityrosinase activity via chelation of copper ions and by disturbing o-quinone production. Furthermore, analyses of the cell cycle, apoptosis rate, and regulation of melanin protein expression revealed preliminarily that PAs could affect melanin production by downregulating microphthalmia transcription factor (MITF) expression and by inhibiting the activities of tyrosinase and tyrosinase related protein 1 (TRP-1), leading to cell cycle arrest and apoptosis of melanoma cells. Collectively, our study demonstrated that PAs are potential tyrosinase inhibitors and have good antimelanoma effects. These findings provide a theoretical support for the application of tyrosinase inhibitors and for further drug development.


Assuntos
Apoptose , Ciclo Celular/efeitos dos fármacos , Melanoma Experimental/patologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Photinia/química , Proantocianidinas/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Expressão Gênica/efeitos dos fármacos , Levodopa/química , Levodopa/metabolismo , Melaninas/biossíntese , Melaninas/genética , Melanoma Experimental/enzimologia , Melanoma Experimental/metabolismo , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Estrutura Molecular , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxirredução , Oxirredutases/genética , Oxirredutases/metabolismo , Ácido Periódico , Folhas de Planta/química , Proantocianidinas/química , Proantocianidinas/isolamento & purificação
20.
Biomolecules ; 11(5)2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946371

RESUMO

Skin hyperpigmentation disorders arise due to excessive production of the macromolecular pigment melanin catalyzed by the enzyme tyrosinase. Recently, the therapeutic use of curcumin for inhibiting tyrosinase activity and production of melanin have been recognized, but poor stability and solubility have limited its use, which has inspired synthesis of curcumin analogs. Here, we investigated four novel chemically modified curcumin (CMC) derivatives (CMC2.14, CMC2.5, CMC2.23 and CMC2.24) and compared them to the parent compound curcumin (PC) for inhibition of in vitro tyrosinase activity using two substrates for monophenolase and diphenolase activities of the enzyme and for diminution of cellular melanogenesis. Enzyme kinetics were analyzed using Lineweaver-Burk and Dixon plots and nonlinear curve-fitting to determine the mechanism for tyrosinase inhibition. Copper chelating activity, using pyrocatechol violet dye indicator assay, and antioxidant activity, using a DPPH radical scavenging assay, were also conducted. Next, the capacity of these derivatives to inhibit tyrosinase-catalyzed melanogenesis was studied in B16F10 mouse melanoma cells and the mechanisms of inhibition were elucidated. Inhibition mechanisms were studied by measuring intracellular tyrosinase activity, cell-free and intracellular α-glucosidase enzyme activity, and effects on MITF protein level and cAMP maturation factor. Our results showed that CMC2.24 showed the greatest efficacy as a tyrosinase inhibitor of all the CMCs and was better than PC as well as a popular tyrosinase inhibitor-kojic acid. Both CMC2.24 and CMC2.23 inhibited tyrosinase enzyme activity by a mixed mode of inhibition with a predominant competitive mode. In addition, CMC2.24 as well as CMC2.23 showed a comparable robust efficacy in inhibiting melanogenesis in cultured melanocytes. Furthermore, after removal of CMC2.24 or CMC2.23 from the medium, we could demonstrate a partial recovery of the suppressed intracellular tyrosinase activity in the melanocytes. Our results provide a proof-of-principle for the novel use of the CMCs that shows them to be far superior to the parent compound, curcumin, for skin depigmentation.


Assuntos
Curcumina/análogos & derivados , Curcumina/farmacologia , Melaninas/biossíntese , Melanócitos/efeitos dos fármacos , Melanoma/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , AMP Cíclico/metabolismo , Cinética , Melanócitos/metabolismo , Camundongos , Fator de Transcrição Associado à Microftalmia/efeitos dos fármacos , Fator de Transcrição Associado à Microftalmia/metabolismo , Oxirredução/efeitos dos fármacos , Oxirredutases/efeitos dos fármacos , Oxirredutases/metabolismo
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