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1.
Biochem Mol Biol Educ ; 49(3): 361-371, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33426769

RESUMO

Due to its distinct phenotype and relatively simple inheritance pattern, the phenylthiocarbamide (PTC) loci is frequently utilized in teaching laboratories to demonstrate genetic concepts such as Mendelian inheritance and population genetics. We have developed a next-generation sequencing and bioinformatics approach to analyze the PTC gene locus to reveal single nucleotide polymorphism (SNP) variation at nucleotide position 785 that predicts tasting ability in humans. Here students purify DNA from their own cheek cells, perform polymerase chain reaction (PCR) amplification of the PTC gene followed by cleaved amplified polymorphic sequence (CAPS) testing. Students perform a second PCR on the PTC loci using high-fidelity Taq to create bar-coded amplicons for next-generation sequencing on the Ion Torrent Personal Genome Machine. Bioinformatic verification reveals polymorphic variation by aligning the entire class PTC PCR fragment sequence to the human gene using Bowtie2 and visualizing the results in the Integrated Genome Viewer. This exercise presents a learning opportunity for students to use next-generation sequencing to predict their own PTC taste sensitivity phenotype coupled with the standard CAPS method. This approach brings the PTC teaching method into the genomics era.


Assuntos
Biologia Computacional/métodos , Genômica/métodos , Laboratórios/normas , Feniltioureia/metabolismo , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único , Paladar/fisiologia , Biologia Computacional/educação , Genômica/educação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Feniltioureia/química
2.
Behav Res Methods ; 53(2): 864-873, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32885386

RESUMO

The sense of taste is rarely assessed quantitatively outside of a limited number of academic and industrial laboratories, despite its role in influencing nutrition, the flavor of foods and beverages, and protection against ingestion of spoiled and toxic foodstuffs. This dearth reflects, in part, practical limitations of most taste tests, most notably their reliance on liquid stimuli for stimulus presentation or rinsing. In this study, a novel portable taste test that requires neither liquid tastants nor liquid rinses is described and validated within a clinic population. This test, termed the Waterless Empirical Taste Test (WETT®), uses stimuli that are embedded in pads of monometer cellulose located on disposable plastic strips applied to the tongue's surface. The test-retest and split-half reliability coefficients of the WETT® were 0.92 and 0.88, respectively. These respective coefficients for sucrose, NaCl, citric acid, caffeine, and MSG were 0.82 and 0.80, 0.78 and 0.77, 0.56 and 0.73, and 0.84 and 0.84. The WETT® exhibited comparable, in some cases higher, sensitivity than two comparison taste tests, the Whole Mouth Taste Test and the Taste Quadrant Taste Test, to age, sex, etiology (head trauma vs. upper respiratory infections), and phenylthiocarbamide (PTC) taste ability. This study demonstrates that a taste test that does not require liquids can be as reliable and sensitive as more traditional liquid-based taste tests to clinical alterations in taste function.


Assuntos
Feniltioureia , Paladar , Humanos , Reprodutibilidade dos Testes , Sacarose
3.
Bioorg Med Chem Lett ; 30(17): 127409, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738979

RESUMO

Infections caused by Pseudomonas aeruginosa become increasingly difficult to treat because these bacteria have acquired various mechanisms for antibiotic resistance, which creates the need for mechanistically novel antibiotics. Such antibiotics might be developed by targeting enzymes involved in the iron uptake mechanism because iron is essential for bacterial survival. For P. aeruginosa, pyoverdine has been described as an important virulence factor that plays a key role in iron uptake. Therefore, inhibition of enzymes involved in the pyoverdine synthesis, such as PvdP tyrosinase, can open a new window for the treatment of P. aeruginosa infections. Previously, we reported phenylthiourea as the first allosteric inhibitor of PvdP tyrosinase with high micromolar potency. In this report, we explored structure-activity relationships (SAR) for PvdP tyrosinase inhibition by phenylthiourea derivatives. This enables identification of a phenylthiourea derivative (3c) with a potency in the submicromolar range (IC50 = 0.57 + 0.05 µM). Binding could be rationalized by molecular docking simulation and 3c was proved to inhibit the bacterial pyoverdine production and bacterial growth in P. aeruginosa PA01 cultures.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oligopeptídeos/metabolismo , Feniltioureia/análogos & derivados , Regulação Alostérica/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Desenho de Fármacos , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/metabolismo , Cinética , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/metabolismo , Oligopeptídeos/química , Feniltioureia/metabolismo , Feniltioureia/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/fisiologia , Relação Estrutura-Atividade
4.
Artigo em Inglês | MEDLINE | ID: mdl-32785183

RESUMO

Phenylthiocarbamide (PTC) is a bitter compound that is similar in taste to the polyphenols present in most vegetables and fruits. The human taste response towards this compound influences dietary preference, which has a bearing on an individual's body mass index (BMI). Another factor that influences taste perception is fungiform papillae count. This, in turn, is governed by genetic factors or deleterious habits such as smoking. Establishing a link between all the above factors could lead to a wider understanding of obesity, which is a global health issue. PTC taste response, BMI, and fungiform papillae were recorded and statistically analyzed between two groups-smokers and nonsmokers. There was no statistically significant difference between smokers and nonsmokers with regard to PTC tasting ability. However, there was a significant inverse relationship between BMI and PTC tasting ability and fungiform papillae count both in smokers and nonsmokers. Thus, it can be inferred that as BMI increases, there is a lower likelihood of experiencing the bitter taste of PTC. Additionally, the ability to taste PTC decreases with diminishing numbers of fungiform papillae. Smoking does not affect bitter PTC tasting ability despite negatively affecting fungiform papillae count.


Assuntos
não Fumantes , Feniltioureia , Fumantes , Paladar , Índice de Massa Corporal , Humanos , Arábia Saudita/epidemiologia , Língua
5.
Pharmacol Res ; 159: 105039, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32565313

RESUMO

The gasotransmitter hydrogen sulfide (H2S) is involved in the regulation of the vascular tone and an impairment of its endogenous production may play a role in hypertension. Thus, the administration of exogenous H2S may be a possible novel and effective strategy to control blood pressure. Some natural and synthetic sulfur compounds are suitable H2S-donors, exhibiting long-lasting H2S release; however, novel H2S-releasing agents are needed to improve the pharmacological armamentarium for the treatment of cardiovascular diseases. For this purpose, N-phenylthiourea (PTU) and N,N'-diphenylthiourea (DPTU) compounds have been investigated as potential H2S-donors. The thioureas showed long-lasting H2S donation in cell free environment and in human aortic smooth muscle cells (HASMCs). In HASMCs, DPTU caused membrane hyperpolarization, mediated by activation of KATP and Kv7 potassium channels. The thiourea derivatives promoted vasodilation in rat aortic rings, which was abolished by KATP and Kv7 blockers. The vasorelaxing effects were also observed in angiotensin II-constricted coronary vessels. In conclusion, thiourea represents an original H2S-donor functional group, which releases H2S with slow and long lasting kinetic, and promotes typical H2S-mediated vascular effects. Such a moiety will be extremely useful for developing original cardiovascular drugs and new chemical tools for investigating the pharmacological roles of H2S.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Feniltioureia/farmacologia , Tioureia/análogos & derivados , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Humanos , Preparação de Coração Isolado , Canais KATP/agonistas , Canais KATP/metabolismo , Canais de Potássio KCNQ/agonistas , Canais de Potássio KCNQ/metabolismo , Masculino , Potenciais da Membrana , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Ratos Wistar , Tioureia/farmacologia
6.
J Econ Entomol ; 113(3): 1419-1425, 2020 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-32173761

RESUMO

The diamondback moth, Plutella xylostella (L.), is a worldwide insect pest of cruciferous crops. Although insecticides have long been used for its control, diamondback moth rapidly evolves resistance to almost any insecticide. In insects, juvenile hormone (JH) is critically involved in almost all biological processes. The correct activity of JH depends on the precise regulation of its titer, and juvenile hormone esterase (JHE) is the key regulator. Thus, JH and JHE have become important targets for new insecticide development. Trifluoromethyl ketones are specific JHE inhibitors, among which 3-octylthio-1,1,1-trifluoropropan-2-one (OTFP) has the highest activity. The interaction effects between pretreatment with or combination of OTFP and the insecticides diafenthiuron, indoxacarb, and Bacillus thuringiensis (Bt) were investigated in diamondback moth larvae to determine OTFP's potential as an insecticide synergist. In third-instar larvae, both pretreatment and combination treatment with OTFP decreased or antagonized the toxicities of diafenthiuron, indoxacarb, and Bt at all set concentrations. In fourth-instar larvae, combination treatment with OTFP decreased or antagonized the toxicities of diafenthiuron and indoxacarb at all set concentrations. However, it increased or synergized the toxicity of Bt at lower concentrations despite the limited effect at higher concentrations. Our results indicated that the effect of OTFP on the toxicities of insecticides varied with the type and concentration, larval stage, and treatment method. These findings contribute to the better use of OTFP in diamondback moth control.


Assuntos
Bacillus thuringiensis , Inseticidas , Mariposas , Acetona/análogos & derivados , Animais , Resistência a Inseticidas , Inseticidas/farmacologia , Larva , Oxazinas , Feniltioureia/análogos & derivados
7.
Primates ; 61(3): 485-494, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32006126

RESUMO

Bitter taste perception enables the detection of potentially toxic molecules and thus evokes avoidance behavior in vertebrates. It is mediated by bitter taste receptors, TAS2Rs. One of the best-studied TAS2R is TAS2R38. Phenylthiocarbamide (PTC) perception and TAS2R38 receptors vary across primate species, and this variation may be related to variation in dietary preferences. In particular, we previously found that the low sensitivity of TAS2R38s in Asian colobines likely evolved as an adaptation to their leaf-eating behavior. However, it remains unclear whether this low PTC sensitivity is a general characteristic of the subfamily Colobinae, a primate group that feeds predominantly on leaves. We performed genetic analyses, functional assays with mutant proteins, and behavioral analyses to evaluate the general characteristics of TAS2R38 in colobines. We found that PTC sensitivity is lower in TAS2R38s of African colobines than in TAS2R38s of omnivorous macaques. Furthermore, two amino acids shared between Asian and African colobines were responsible for low sensitivity to PTC, suggesting that the last common ancestor of extant colobines had this phenotype. We also detected amino acid differences between TAS2R38s in Asian and African colobines, indicating that they evolved independently after the separation of these groups.


Assuntos
Colobinae/genética , Evolução Molecular , Feniltioureia/metabolismo , Receptores Acoplados a Proteínas G/genética , Percepção Gustatória/genética , Animais , Feminino , Masculino
8.
Int J Mol Sci ; 21(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019241

RESUMO

Tyrosinase-related protein 1 (TYRP1) is one of the three human melanogenic enzymes involved in the biosynthesis of melanin, a pigment responsible for the color of the skin, hair, and eyes. It shares high sequence identity with tyrosinase, but has two zinc ions in its active site rather than two copper ions as in tyrosinase. Typical tyrosinase inhibitors do not directly coordinate to the zinc ions of TYRP1. Here, we show, from an X-ray crystal structure determination, that phenylthiourea, a highly potent tyrosinase inhibitor, does neither coordinate the active site zinc ions, but binds differently from other structurally characterized TYRP1-inhibitor complexes. Its aromatic ring is directed outwards from the active site, apparently as a result from the absence of polar oxygen substituents that can take the position of water molecules bound in the active site. The compound binds via hydrophobic interactions, thereby blocking substrate access to the active site.


Assuntos
Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Oxirredutases/química , Oxirredutases/metabolismo , Feniltioureia/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Humanos , Modelos Moleculares , Conformação Proteica
9.
Int J Biol Macromol ; 146: 212-221, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899238

RESUMO

The biosynthesis of pyoverdine, the major siderophore of Pseudomonas aeruginosa, is a well-organized process involving a discrete number of enzyme-catalyzed steps. The final step of this process involves the PvdP tyrosinase, which converts ferribactin into pyoverdine. Thus, inhibition of the PvdP tyrosinase activity provides an attractive strategy to interfere with siderophore synthesis to manage P. aeruginosa infections. Here, we report phenylthiourea as a non-competitive inhibitor of PvdP for which we solved a crystal structure in complex with PvdP. The crystal structure indicates that phenylthiourea binds to an allosteric binding site and thereby interferes with its tyrosinase activity. We further provide proofs that PvdP tyrosinase inhibition by phenylthiourea requires the C-terminal lid region. This provides opportunities to develop inhibitors that target the allosteric site, which seems to be confined to fluorescent pseudomonads, and not the tyrosinase active site. Furthermore, increases the chances to identify PvdP inhibitors that selectively interfere with siderophore synthesis.


Assuntos
Proteínas de Bactérias , Monofenol Mono-Oxigenase , Oligopeptídeos/biossíntese , Feniltioureia , Pseudomonas aeruginosa/enzimologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/metabolismo , Feniltioureia/química , Feniltioureia/farmacologia
10.
J Med Entomol ; 57(2): 454-462, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31559435

RESUMO

Dengue, yellow fever, Zika, and chikungunya arboviruses are endemic in tropical countries and are transmitted by Aedes aegypti. Resistant populations of this mosquito against chemical insecticides are spreading worldwide. This study aimed to evaluate the biological effects of exposure of pesticide-sensitive Ae. aegypti larvae (Rockefeller) to conidia of the entomopathogen, Metarhizium brunneum, laboratory strains ARSEF 4556 and V275, and any synergistic activity of phenylthiourea (PTU). In addition, to investigate the nature of any cross-resistance mechanisms, these M. brunneum strains were tested against the Rockefeller larvae and two temephos- and deltamethrin-resistant wild mosquito populations from Rio de Janeiro. Treatment of Rockefeller larvae with 106 conidia/ml of ARSEF 4556 and V275 fungal strains resulted in significant decreased survival rates to 40 and 53.33%, respectively (P < 0.0001), compared with untreated controls. In contrast, exposure to 104 or 105 conidia/ml showed no such significant survival differences. However, the addition of PTU to the conidia in the bioassays significantly increased mortalities in all groups and induced a molt block. Experiments also showed no differences in Ae. aegypti mortalities between the fungal treated, wild pesticide-resistant populations and the Rockefeller sensitive strain. The results show the efficacy of M. brunneum in controlling Ae. aegypti larvae and the synergistic role of PTU in this process. Importantly, there was no indication of any cross-resistance mechanisms between Ae. aegypti sensitive or resistant to pesticides following treatment with the fungi. These results further support using M. brunneum as an alternative biological control agent against mosquito populations resistant to chemical insecticides.


Assuntos
Aedes/microbiologia , Agentes de Controle Biológico/farmacologia , Controle de Insetos , Resistência a Inseticidas , Inseticidas/farmacologia , Metarhizium/fisiologia , Controle Biológico de Vetores , Aedes/efeitos dos fármacos , Animais , Larva/efeitos dos fármacos , Larva/microbiologia , Organofosfatos/farmacologia , Feniltioureia/farmacologia , Piretrinas/farmacologia
11.
Pestic Biochem Physiol ; 162: 43-51, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31836053

RESUMO

The diamondback moth (DBM), Plutella xylostella (L.), is a major pest affecting cruciferous vegetables, and seriously affects the quality and yield of these vegetables. Diafenthiuron is a traditional thiourea-based insecticide, but it is rarely used to control pests on cruciferous vegetables due to its phytotoxicity on these vegetables under high temperature and light conditions. Thus, there is an ongoing need for more effective pesticides that can be used on cruciferous vegetables, possibly including new formulations of diafenthiuron. A new thiourea insecticide, methylthio-diafenthiuron, is intended to optimize the structure of diafenthiuron not only to preserve its insecticidal bioactivity but also to overcome its phytotoxicity to cruciferous vegetables, aiming to control insect pests on cruciferous vegetables. In this study, we compared the toxicity of methylthio-diafenthiuron to some frequently used insecticides on the third-instar larvae of DBM. The parental pupal duration was significantly longer under the treatment than in the control, but the pupal weight, fecundity, and hatching rate significantly decreased. By studying the changes in three detoxifying enzymes within 72 h after treatment with a sublethal concentration, the activity of CarE and ODM in the treatment group significantly increased at first and then decreased. In addition, methylthio-diafenthiuron clearly inhibited three kinds of ATPases in the DBM and significantly reduced the eclosion rate of the pupae. This research provides valuable information for the assessment and rational application of methylthio-diafenthiuron for the control of pests on cruciferous vegetables.


Assuntos
Mariposas , Animais , Larva , Tábuas de Vida , Feniltioureia/análogos & derivados
12.
REVISA (Online) ; 9(4): 744-753, 2020.
Artigo em Português | LILACS | ID: biblio-1145937

RESUMO

Avaliar a sensibilidade gustativa a proteína PTC nos docentes de uma faculdade privada de Goiás, associando esta sensibilidade gustativa à ingestão de alimentos que contém essa substância, hábitos socioculturais e alimentares. Método: A avaliação da sensibilidade ao composto PTC (Feniltiocarbamida) ocorreu junto a 40 docentes de uma faculdade privada do estado de Goiás após administração oral de uma gota da solução de concentração 0,01% do composto, seguida pela aplicação do questionário para avaliar à substância testada. Os dados foram analisados no programa EpiInfo versão 7.2.3.0. Para se verificar a associação entre a sensibilidade gustativa ao PTC e as variáveis dependentes. utilizou-se os testes do qui-quadrado ou o teste exato de Fisher. Resultados: Observou-se que 65% dos docentes recrutados apresentam sensibilidade ao PTC. De 40 participantes, 47,5% eram do sexo feminino e 52,5% do sexo masculino. A população era da faixa etária entre 24 e 62 anos. Após a administração da solução do composto PTC (0,01%), a sensibilidade ao sabor amargo foi a mais relatada. Não houve associação entre a sensibilidade gustativa ao PTC e as variáveis estudadas. Conclusão: A inclusão na dieta de alimentos considerados saudáveis, associados ao sabor amargo, pode também ser influenciada pelo grau de sensibilidade e tolerância à esses alimentos.


To evaluate the taste sensitivity to PTC protein in the teachers of a private college in Goiás, associating this taste sensitivity to the ingestion of foods that contain this substance, sociocultural and eating habits. Method: The sensitivity assessment to the compound PTC (Phenylthiocarbamide) occurred with 40 teachers from a private college in the state of Goiás after oral administration of a drop of the 0.01% concentration solution of the compound, followed by the application of the questionnaire to evaluate the tested substance. The data were fulfilled using the EpiInfo program version 7.2.3.0. To verify an association between taste sensitivity to PTC and as dependent dependents. chi-square tests or Fisher's exact test are used. Results: It was observed that 65% of the recruited professors are sensitive to PTC. Of the 40 participants, 47.5% were female and 52.5% male. The population was between 24 and 62 years old. After administration of the PTC compound solution (0.01%), sensitivity to bitter taste was the most reported. There was no association between taste sensitivity to PTC and the variables studied. Conclusion: The inclusion in the diet of foods considered considered, associated with the bitter taste, can also be influenced by the degree of sensitivity and tolerance to these foods.


Evaluar la sensibilidad gustativa a la proteína PTC en los profesores de un colegio privado de Goiás, asociando esta sensibilidad gustativa a la ingestión de alimentos que contienen esta sustancia, hábitos socioculturales y alimentarios. Método: La evaluación de sensibilidad al compuesto PTC (Feniltiocarbamida) se realizó con 40 profesores de un colegio privado en el estado de Goiás luego de la administración oral de una gota de la solución de concentración al 0.01% del compuesto, seguida de la aplicación del cuestionario para evaluar la sustancia probada. Los datos se cumplieron utilizando el programa EpiInfo versión 7.2.3.0. Verificar una asociación entre la sensibilidad gustativa a PTC y como dependientes dependientes. Se utilizan pruebas de chicuadrado o la prueba exacta de Fisher. Resultados: Se observó que el 65% de los profesores reclutados son sensibles al PTC. De los 40 participantes, el 47,5% eran mujeres y el 52,5% hombres. La población tenía entre 24 y 62 años. Después de la administración de la solución del compuesto PTC (0,01%), la sensibilidad al sabor amargo fue la más notificada. No hubo asociación entre la sensibilidad gustativa al PTC y las variables estudiadas. Conclusión: La inclusión en la dieta de los alimentos considerados considerados, asociados al sabor amargo, también puede estar influenciada por el grado de sensibilidad y tolerancia a estos alimentos.


Assuntos
Animais , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Feniltioureia , Paladar , Consumo de Bebidas Alcoólicas , Docentes , Alimentos , Dieta Saudável , Fumar Tabaco
13.
Talanta ; 199: 131-139, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952236

RESUMO

Detection and identification of bitter compounds draw great attention in pharmaceutical and food industry. Several well-known agonists of specific bitter taste receptors have been found to exhibit anti-cancer effects. For example, N-C=S-containing compounds, such as allyl-isothiocyanates, have shown cancer chemo-preventive effects. It is worth noting that human T2R38 receptor is specific for compounds containing N-C=S moiety. Here, a bioinspired cell-based bioelctronic tongue (BioET) is developed for the high-specificity isothiocyanate-induced bitter detection, utilizing human Caco-2 cells as a primary sensing element and interdigitated impedance sensor as a secondary transducer. As an intestinal carcinoma cell line, Caco-2 endogenously expresses human bitter receptor T2R38, and the activation of T2R38 induces the changes of cellular morphology which can be detected by electric cell-substrate impedance sensing (ECIS). After configuration and optimization of parameters including timing of compound administration and cell density, quantitative bitter evaluation models were built for two well-known bitter compounds, phenylthiocarbamide (PTC) and propylthiouracil (PROP). The bitter specific detection of this BioET is inhibited by probenecid and U-73122, and is not elicited by other taste modalities or bitter ligands that do not activate T2R38. Moreover, by combining different computational tools, we designed a ligand-based virtual screening (LBVS) protocol to select ligands that are likely to activate T2R38 receptor. Three computationally predicted agonists of T2R38 were selected using the LBVS protocol, and the BioET presented response to the predicted agonists, validating the capability of the LBVS protocol. This study suggests this unique cell-based BioET paves a general and promising way to specifically detect N-C=S-containing compounds that can be used for pharmaceutical study and drug development.


Assuntos
Nariz Eletrônico , Isotiocianatos/análise , Receptores Acoplados a Proteínas G/metabolismo , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Isotiocianatos/farmacologia , Ligantes , Estrutura Molecular , Feniltioureia/química , Feniltioureia/farmacologia , Propiltiouracila/química , Propiltiouracila/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Laryngoscope ; 129(9): E307-E312, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30675726

RESUMO

OBJECTIVES/HYPOTHESIS: Taste sensitivity varies greatly among individuals influencing eating behavior and health, consequently the disorders of this sense can affect the quality of life. The ability to perceive the bitter of thiourea compounds, such as phenylthiocarbamide (PTC), has been largely reported as a marker of the general taste sensitivity, food preferences, and health. PTC sensitivity is mediated by the TAS2R38 receptor and its genetic common variants. We study the role of the TAS2R38 receptor in taste disorders with the aim of understanding if these can be genetically determined. STUDY DESIGN: Prospective cohort study. METHODS: Differences in the PTC responsiveness between the patients cohort and healthy controls were assessed. All subjects received standardized tests for smell and taste function and were genotyped for the TAS2R38 gene. RESULTS: PAV/PAV homozygous patients gave high PTC ratings, whereas PAV/AVI genotypes reported lower values, which are similar to those determined in AVI/AVI or rare genotypes. In addition, the patients cohort did not meet the Hardy-Weinberg equilibrium at the TAS2R38 locus, showing a very low frequency of subjects carrying the PAV/AVI diplotype. Independently, in healthy controls who were in equilibrium at the locus, PAV/PAV homozygous and heterozygous rated PTC bitterness higher compared to AVI/AVI or rare genotypes. CONCLUSIONS: Our findings, by showing that an only taster haplotype (PAV) is not sufficient to evoke high responses of TAS2R38 receptor in patients with taste disorders, suggest that the genetic constitution may represent a risk factor for the development of taste disorders. LEVEL OF EVIDENCE: 2c Laryngoscope, 129:E307-E312, 2019.


Assuntos
Receptores Acoplados a Proteínas G/análise , Distúrbios do Paladar/genética , Paladar/genética , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Feniltioureia/análise , Projetos Piloto , Estudos Prospectivos , Saliva/química
15.
Eur Arch Otorhinolaryngol ; 276(3): 753-759, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30604062

RESUMO

PURPOSE: In clinical practice, when ability to perceive bitter taste is studied, quinine is preferred to phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) as taste stimulus, because many subjects are genetically non-tasters for PTC/PROP. However, it is poorly known how sensitive anterior (front) and posterior (back) parts of the tongue are to different bitter tastants that are detected by different bitter taste receptors (TAS2Rs). In the present study, we aimed to characterize sensitivity to bitter taste at front and back parts of tongue. METHODS: We measured thresholds for quinine, PTC, and PROP using the "taste strips", employing seven concentrations of each stimulus both at front and back parts of tongue in 203 healthy participants (56% females, mean age 28 years). RESULTS: Our data confirmed the hypothesis that the inability to perceive quinine was less frequent than the inability to perceive PTC and PROP: People can still perceive the bitter taste of quinine even if they are "non-tasters" for PROP/PTC. As expected, strong correlations between PTC and PROP thresholds were observed. Interestingly, correlations between thresholds for quinine and PTC/PROP also emerged. Overall, the detection thresholds were lower when measured at front part of the tongue. CONCLUSIONS: Our data suggest that determining taster status for quinine using paper "taste strips", applied to front part of the tongue, represents a suitable method for the screening for ageusia for bitter taste.


Assuntos
Feniltioureia , Propiltiouracila , Quinina , Percepção Gustatória/fisiologia , Limiar Gustativo , Língua/fisiologia , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Percepção Gustatória/efeitos dos fármacos , Língua/anatomia & histologia , Adulto Jovem
16.
J Diet Suppl ; 16(1): 40-50, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29521557

RESUMO

Oral nutritional supplements (ONS) are frequently prescribed for those at risk of malnutrition. Palatability is an important factor in long-term compliance. ONS selection is typically dietitian led, but the degree to which individual perceptions of palatability influence dietitian clinical decision making is unclear. This study aimed to explore factors that influence dietitians' ONS clinical practice, evaluate dietitian hedonic preferences and overall impression of specific ONS products, and study phenylthiocarbamide (PTC) sensitivity in relation to ONS hedonic ratings. Dietitians were recruited from six urban teaching hospitals. They completed a 10-item Clinical Practices Questionnaire prior to taste testing five samples of three ONS products. A 7-point hedonic Likert scale recorded ONS palatability ratings. A PTC test was conducted. Thirty-one dietitians were recruited. Nutritional value, patient palatability, patient acceptability, tolerance and hospital contracts were the factors identified as most likely to influence ONS prescription. All ONS were consistently highly rated for overall impression. The high-protein ONS was most highly rated for all hedonic characteristics. Taste was the highest rated hedonic characteristic across all products. No statistically significant relationship was found between PTC sensitivity and ONS overall impression. The key drivers of ONS dietitian clinical practice were identified. ONS hedonic characteristics and overall impression were highly rated, which suggested this range of products had wide appeal for dietetic professionals. The taste and consistency of the ONS were rated better than other hedonic characteristics (appearance, smell, aftertaste).


Assuntos
Tomada de Decisões , Suplementos Nutricionais/análise , Nutrientes/administração & dosagem , Nutricionistas , Paladar , Administração Oral , Adulto , Proteínas na Dieta/administração & dosagem , Feminino , Humanos , Masculino , Nutrientes/uso terapêutico , Valor Nutritivo , Satisfação do Paciente , Feniltioureia , Inquéritos e Questionários
17.
J Biochem Mol Toxicol ; 32(12): e22221, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30291660

RESUMO

In the presence of trifluoroacetic acid, on the basis of three-component condensation of phenylthiourea with its salicylaldehyde and methyl-3-oxobutanoate, an efficient method for the synthesis of 1-(4-(2-hydroxyphenyl)-6-methyl-1-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone (I) has been worked out. These novel N-substituted tetrahydropyrimidines based on phenylthiourea showed good inhibitory action against acetylcholinesterase (AChE), α-glycosidase, and human carbonic anhydrase (hCA) isoforms I and II. K i values of AChE enzyme were in the range of 0.48 to 7.46 nM. The hCA I and II were effectively inhibited by the compounds, with K i values in the range of 502.44 to 923.11 nM for hCA I and 400.32 to 801.57 nM for hCA II, respectively. The antioxidant activity of the novel N-substituted tetrahydropyrimidines based on phenylthiourea was investigated by using different in vitro antioxidant assays; including 1,1-diphenyl-2-picrylhydrazyl (DPPH·) radical scavenging, Cu 2+  and Fe 3+ reducing activities.


Assuntos
Anticonvulsivantes/farmacologia , Antioxidantes/farmacologia , Antagonistas Colinérgicos/farmacologia , Hipoglicemiantes/farmacologia , Feniltioureia/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Colinesterase/farmacologia , Cristalografia por Raios X , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Humanos , Isoenzimas/antagonistas & inibidores , Modelos Moleculares , Feniltioureia/química , Espectroscopia de Prótons por Ressonância Magnética , Pirimidinas/química , Relação Estrutura-Atividade
18.
Molecules ; 23(10)2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30248936

RESUMO

4-Chloro-3-nitrophenylthioureas 1⁻30 were synthesized and tested for their antimicrobial and cytotoxic activities. Compounds exhibited high to moderate antistaphylococcal activity against both standard and clinical strains (MIC values 2⁻64 µg/mL). Among them derivatives with electron-donating alkyl substituents at the phenyl ring were the most promising. Moreover, compounds 1⁻6 and 8⁻19 were cytotoxic against MT-4 cells and various other cell lines derived from human hematological tumors (CC50 ≤ 10 µM). The influence of derivatives 11, 13 and 25 on viability, mortality and the growth rate of immortalized human keratinocytes (HaCaT) was observed.


Assuntos
Antibacterianos/farmacologia , Queratinócitos/citologia , Feniltioureia/análogos & derivados , Antibacterianos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Queratinócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus/efeitos dos fármacos , Testes de Toxicidade
19.
Sci Rep ; 8(1): 11332, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30054507

RESUMO

Cell death by hypoxia followed by reoxygenation (H/R) is responsible for tissue injury in multiple pathological conditions. Recent studies found that epigenetic reprogramming mediated by histone deacetylases (HDACs) is implicated in H/R-induced cell death. However, among 18 different isoforms comprising 4 classes (I-IV), the role of each HDAC in cell death is largely unknown. This study examined the role of HDAC8, which is the most distinct isoform of class I, in the hypoxia mimetic cobalt- and H/R-induced cytotoxicity of human proximal tubular HK-2 cells. Using the HDAC8-specific activator TM-2-51 (TM) and inhibitor PCI34051, we found that HDAC8 played a protective role in cytotoxicity. TM or overexpression of wild-type HDAC8, but not a deacetylase-defective HDAC8 mutant, prevented mitochondrial fission, loss of mitochondrial transmembrane potential and release of cytochrome C into the cytoplasm. TM suppressed expression of dynamin-related protein 1 (DRP1) which is a key factor required for mitochondrial fission. Suppression of DRP1 by HDAC8 was likely mediated by decreasing the level of acetylated histone H3 lysine 27 (a hallmark of active promoters) at the DRP1 promoter. Collectively, this study shows that HDAC8 inhibits cytotoxicity induced by cobalt and H/R, in part, through suppressing DRP1 expression and mitochondrial fission.


Assuntos
Cobalto/toxicidade , Citoproteção , Histona Desacetilases/metabolismo , Túbulos Renais Proximais/patologia , Dinâmica Mitocondrial , Oxigênio/farmacologia , Proteínas Repressoras/metabolismo , Acetilação , Benzamidas/farmacologia , Morte Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Citoproteção/efeitos dos fármacos , Dinaminas , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Lisina/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Feniltioureia/análogos & derivados , Feniltioureia/farmacologia , Regiões Promotoras Genéticas/genética , Quinazolinonas/farmacologia
20.
Spectrochim Acta A Mol Biomol Spectrosc ; 205: 146-159, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30015020

RESUMO

A novel bis-[1-(2-[(2-hydroxynaphthalen-1-yl) methylidene]amino}ethyl)-1-ethyl-3-phenylthiourea] Schiff base (L) and its binuclear palladium and ruthenium complexes have been prepared and characterized by ESI-MS, elemental analysis, NMR (1H NMR, 13C NMR, COSY, NEOSY and HSQC), FT-IR, ATR, UV-Visible spectra, TGA measurements, conductivity and cyclic voltammetry. The experimental results and the molecular parameters calculated using DFT method revealed a square planar geometry around Pd and octahedral geometry around ruthenium metal. The antibacterial activity of the ligand L and its complexes was evaluated against different human bacteria. In addition, the formation constants of the synthesized Schiff base-metal complexes and the systems formed with these chelates and cholesterol were estimated using spectrophotometric technique. The detection of cholesterol using novel Pd and Ru Schiff base complexes was studied using fluorometric method, and the measurements showed that the sensitive fluorometric response towards cholesterol analysis was determined using palladium complex. The limit of detection (LOD) of cholesterol calculated using this complex (4.6 µM) is lower (better) than LOD found using ruthenium complex (19.1 µM) and different compounds previously published around linear range of 0-5 mM.


Assuntos
Antibacterianos/química , Antioxidantes/química , Paládio/química , Feniltioureia/química , Rutênio/química , Bases de Schiff/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Colesterol/análise , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Modelos Moleculares , Feniltioureia/síntese química , Feniltioureia/farmacologia , Reprodutibilidade dos Testes , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Análise Espectral
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