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1.
Adv Food Nutr Res ; 91: 157-225, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32035596

RESUMO

Fruits and vegetables are essential for human nutrition, delivering a substantial proportion of vitamins, minerals, and fibers in our daily diet. Unfortunately, half the fruits and vegetables produced worldwide end up as wastes, generating environmental issues caused mainly by microbial degradation. Most wastes are generated by industrial processing, the so-called by-products. These by-products still contain many bioactive compounds post-processing, such as macronutrients (proteins and carbohydrates) and phytochemicals (polyphenols and carotenoids). Recently, the recovery of these bioactive compounds from industry by-products has received significant attention, mainly due to their possible health benefits for humans. This chapter focuses on the bioactive potential of fruit and vegetable by-products with possible applications in the food industry (functional foods) and in the health sector (nutraceuticals).

2.
Appetite ; 143: 104416, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31473275

RESUMO

BACKGROUND: Adolescence is a critical stage in life course development. It is a particularly relevant stage regarding our understanding of eating behaviors since adolescent's evolving, more autonomous food preferences tend to be influenced by peers and media as much if not more than the family. Therefore, exploring adolescent's eating preferences could be an important focus to developing prevention programs. AIMS: To explore the role of psychological variables (namely, self-risk perception, self-control and eating motivations) and their relationships with healthy eating attitudes. METHODS: A sample of adolescents (Szeged, Hungary, N = 274, ages 14-19 years; mean age = 15.95 years, S.D. = 1.17 years; 54% males) was recruited to participate in the study. Data were collected from self-administered/anonymous questionnaires. Besides descriptive statistics, correlations and a path analysis were applied to examine the relationships between self-control, self-risk perception, eating motivations and healthy eating attitudes. RESULTS: Self-control played a decisive role, both directly and indirectly in healthy eating attitudes, while self-risk-perception had a less important mediating role. Eating motives were directly related to eating attitudes but in a different way: health motives were positively associated with healthy eating attitudes, while social and external motives had a negative relationship. CONCLUSIONS: The path analysis suggests that self-control indeed plays an important role in developing healthy attitudes. While health motives play a more decisive role in health-related attitudes than we might expect, self-risk perception plays a limited role perhaps due to the notion that adolescents typically present a feeling of invulnerability. These findings suggest that despite their diminished self-risk perception, adolescents tend to be health conscious in nutrition, particularly when it combines with the underlying impact of self-control and health motives.

3.
Antioxidants (Basel) ; 8(8)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398838

RESUMO

Global tomato production is currently around 180 million tons, of which more than a quarter undergoes processing. The removed peels, seeds, and vascular tissues usually end up in landfills, creating environmental pollution. In order to highlight the alternative use of these vegetal wastes, our study investigated 10 tomato varieties in terms of carotenoids content, phenolic composition, and their related antioxidant and antimicrobial activities. Tomato peels extracts were screened by high performance liquid chromatography with diode-array detection (HPLC/DAD) for qualitative and quantitative analyses. The extracts were tested against six bacterial strains to determine their antimicrobial effect; the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay was applied to estimate their antioxidant capacity. Total carotenoids content was significantly higher in Taranești roz, a local variety (5.31 ± 0.12 mg/100 g DW), while Mirsini, a commercial hybrid, presented significantly higher total phenolic content (155 ± 2 mg/100 g DW) compared to the mean value of all analyzed samples. The methanolic extracts of tomato peels presented acceptable antimicrobial activity against Staphilococcus aureus and Bacillus subtilis, and the mean antioxidant activity was 201 ± 44 µmol Trolox/100 g DW tomato peels. Considering that tomato peels have lycopene, ß-carotene, lutein, and different phenolic compounds in their composition, tomato industrial by-products could represent a source of natural bioactive molecules with applicability in nutraceuticals and food industry.

4.
J Med Chem ; 62(13): 6116-6136, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31251604

RESUMO

Epimeric series of aryl-substituted glucopyranosylidene-spiro-imidazolinones, an unprecedented new ring system, were synthesized from the corresponding Schiff bases of O-perbenzoylated (gluculopyranosylamine)onamides by intramolecular ring closure of the aldimine moieties with the carboxamide group elicited by N-bromosuccinimide in pyridine. Test compounds were obtained by Zemplén O-debenzoylation. Stereochemistry and ring tautomers of the new compounds were investigated by NMR, time-dependent density functional theory (TDDFT)-electronic circular dichroism, and DFT-NMR methods. Kinetic studies with rabbit muscle and human liver glycogen phosphorylases showed that the (R)-imidazolinones were 14-216 times more potent than the (S) epimers. The 2-naphthyl-substituted (R)-imidazolinone was the best inhibitor of the human enzyme (Ki 1.7 µM) and also acted on HepG2 cells (IC50 177 µM). X-ray crystallography revealed that only the (R) epimers bound in the crystal. Their inhibitory efficacy is based on the hydrogen-bonding interactions of the carbonyl oxygen and the NH of the imidazolinone ring.

5.
Molecules ; 24(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146359

RESUMO

Some species of the Ericaceae family have been intensively studied because of the beneficial health impact, known since ancient times, of their chemical components. Since most studies focus on the effects of fruit consumption, this review aims to highlight the phenolic components present in the leaves. For this purpose, five species from Ericaceae family (bilberry-Vaccinium myrtillus L., lingonberry-V. vitis-idaea L., bog bilberry-V. uliginosum L., blueberry-V. corymbosum L. and bearberry-Arctostapylos uva-ursi L.) were considered, four of which can be found in spontaneous flora. The chemical composition of the leaves revealed three major phenolic compounds: chlorogenic acid, quercetin and arbutin. The health promoting functions of these compounds, such as antioxidant and anti-inflammatory properties that could have preventive effects for cardiovascular disease, neurodegenerative disorders, cancer, and obesity, have been exemplified by both in vitro and in vivo studies in this review. Furthermore, the importance of bioaccessibility and bioavailability of the phenolic compounds have been summarized. The findings highlight the fact that leaves of some Ericaceae species deserve increased attention and should be studied more profoundly for their biological activities, especially those from spontaneous flora.


Assuntos
Ericaceae/química , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Animais , Disponibilidade Biológica , Ericaceae/classificação , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia
6.
Eur J Med Genet ; 62(8): 103669, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082515

RESUMO

Preimplantation genetic testing for aneuploidy (PGT-A) is a suitable technique to identify euploid embryos, which have the highest potential to implant, thus increase the chance of a healthy live birth. The main indications of PGT-A are advanced maternal age, repeated implantation failure, repeated miscarriages and severe male infertility. Several studies have already proven that testing embryos for genetic abnormalities in the above cases results in higher implantation rate and reduced number of pregnancy loss. In spite of these - due to a legislative change in Hungary in 2015 - PGT-A was reclassified as an experimental procedure and its use became banned throughout the country. For this reason, after 4 years of successful practice, Hungarian patients were not able to participate in IVF procedure combined with PGT-A anymore. In this retrospective analysis, efficacy of PGT-A-based embryo selection was evaluated and was compared to the conventional morphology-based selection (MBS) in patients with advanced maternal age, between 2013 and 2017 at our private fertility clinic. PGT-A was performed with array comparative genomic hybridization. We found that implantation rate was significantly higher (43.62% vs. 27.88%; p = 0.0208) and miscarriage rate was significantly lower (17.07% vs. 37.93%; p = 0.0492) in the PGT-A group compared to the MBS group from 2013 to 2015. These outcomes were achieved with a significantly lower number of transferred embryos in the PGT-A group (1.25 vs. 1.58; p = 0.0003). In 2016-2017, the number of transferred embryos were significantly reduced in the MBS group as well (1.14 vs. 1.58; p < 0.0001). However, outcomes of the IVF treatments did not change significantly compared to the previous two years (2013-2015). Our results imply that PGT-A-based embryo selection is more efficient than morphology-based selection in patients with advanced maternal age. Therefore, prohibition of the use of PGT-A had significant consequences on the efficiency and safety of IVF treatment in the country.


Assuntos
Aborto Espontâneo/diagnóstico , Aneuploidia , Fertilização In Vitro/métodos , Diagnóstico Pré-Implantação , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/genética , Aborto Espontâneo/patologia , Adulto , Blastocisto/metabolismo , Blastocisto/patologia , Hibridização Genômica Comparativa , Transferência Embrionária/métodos , Feminino , Humanos , Hungria/epidemiologia , Assistência ao Paciente , Gravidez
7.
Anim Sci J ; 90(6): 769-773, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30977236

RESUMO

Polyunsaturated fatty acid consumption has been shown to improve insulin sensitivity. We studied if administration of broth with beef meat enriched with polyunsaturated fatty acids influenced glucose-stimulated insulin release in healthy male volunteers. Broth was made either from cattles undergone dietary supplementation with lightly bruised whole linseed in addition to feeding ad libitum on grass silage (test meal) or from those fed grass silage alone (control meal). Oral glucose tolerance tests (OGTT) were performed in patients after a 6-day period of eating 300 ml broth containing 100 g meat once a day in addition to their otherwise normal mixed nourishment. During OGTT, blood samples were taken for blood glucose level and plasma insulin immunoreactivity before and 15, 30, 60, 90, 120, and 180 min after the glucose load. Glucose-stimulated maximum increase in plasma insulin immunoreactivity was 42 ± 6.6 and 81 ± 7.4 mU/ml (p < 0.05) after the test and the control meals, respectively. However, both fasting and postload blood glucose levels were the same after either meal period. The results suggest an insulin-sensitizing effect of food produced from beef cattle maintained on linseed diet in healthy human volunteers.


Assuntos
Ácidos Graxos Insaturados/farmacologia , Linho , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Carne/análise , Silagem , Adulto , Glicemia/metabolismo , Ácidos Graxos Insaturados/isolamento & purificação , Teste de Tolerância a Glucose , Humanos , Masculino , Adulto Jovem
8.
Biomed Res Int ; 2018: 6416378, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30498759

RESUMO

The aim of this study was to determine the clinical, serological, and genetic features of anti-Jo-1 positive antisynthetase patients followed by a Hungarian single centre to identify prognostic markers, which can predict disease phenotypes and disease progression. It was a retrospective study using clinical database of 49 anti-Jo-1 positive patients. 100% of patients exhibited myositis, 73% interstitial lung disease, 88% arthritis, 65% Raynaud's phenomenon, 43% fever, 33% mechanic's hand, and 12% dysphagia. We could detect significant correlation between anti-Jo-1 titer and the CK and CRP levels at disease onset and during disease course. HLA DRB1⁎03 positivity was present in 68.96% of patients, where the CK level at diagnosis was significantly lower compared to the HLA DRB1⁎03 negative patients. HLA DQA1⁎0501-DQB1⁎0201 haplotype was found in 58.62% of patients, but no significant correlation was found regarding any clinical or laboratory features. Higher CRP, ESR level, RF positivity, and the presence of fever or vasculitic skin lesions at the time of diagnosis indicated a higher steroid demand and the administration of higher number of immunosuppressants during the follow-up within anti-Jo-1 positive patients. The organ involvement of the disease was not different in HLA-DRB1⁎0301 positive or negative patients who were positive to the anti-Jo-1 antibody; however, initial CK level was lower in HLA-DRB1⁎0301 positive patients. Distinct laboratory and clinical parameters at diagnosis could be considered as prognostic markers.


Assuntos
Progressão da Doença , Miosite/genética , Miosite/patologia , Adulto , Anticorpos Antinucleares/sangue , Autoanticorpos , Proteína C-Reativa/metabolismo , Estudos de Coortes , Creatina Quinase/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Hungria , Masculino , Metilprednisolona/uso terapêutico , Miosite/sangue , Miosite/tratamento farmacológico , Ribonucleoproteínas/sangue
9.
Orv Hetil ; 159(51): 2183-2192, 2018 12.
Artigo em Húngaro | MEDLINE | ID: mdl-30556408

RESUMO

INTRODUCTION: Nutrition is one of the key factors in health maintainance. So developing appropriate eating habits is very important in adolescence. Dietary behaviour may be influenced by certain aspects of personality, e.g., self-efficacy, optimism/pessimism and self-control. AIM: We explored adolescents' eating behaviour, attitudes, and information seeking, and their relationship with psychological and sociodemographic factors. METHOD: Participants were high school students (n = 277; 54% boys; mean age: 16 years; SD = 1.25). Our self-administered questionnaire contained items on sociodemographics, eating behaviour and attitudes, and information-seeking as well as three psychological scales. RESULTS: We explored the main factors of behaviour (health-conscious, nonconscious, raw-based), attitudes (rejecting, ambivalent and accepting), and information-seeking (lay, professional, Internet) using factor analysis. Correlation analyses revealed adolescents' nutrition-related behaviour and attitudes were rather health-conscious, but rejecting and ambivalence in their behaviour and attitudes appeared as well. Self-efficacy, self-control and optimism played a role not only in developing health-conscious behaviour and accepting attitude but also in avoiding the nonconscious behaviour and rejecting attitude. Health-conscious behaviour was associated with higher socioeconomic status and parents' schooling but less with gender. Information-seeking was partly influenced by certain sociodemographics: professional resources were preferred by girls, students from grammar schools, and those with better school achievement. CONCLUSIONS: Our data draw attention to the extraordinary importance of mapping adolescent dietary habits; not only their behaviours but also attitudes and information-seeking. This life period is significant in terms of childhood nutrional socialization since youth's decisions become more and more autonomous in this field as well. Orv Hetil. 2018; 159(51): 2183-2192.


Assuntos
Comportamento do Adolescente/psicologia , Atitude Frente a Saúde , Comportamento Alimentar/psicologia , Comportamentos Relacionados com a Saúde , Comportamento de Busca de Informação , Estado Nutricional , Adolescente , Feminino , Humanos , Hungria , Masculino , Autoeficácia , Classe Social , Estudantes/psicologia
10.
Plant Foods Hum Nutr ; 73(4): 268-277, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30264237

RESUMO

Alongside paper, plastic, metal and glass, an important segment in the recycling area is represented by the wastes of different vegetal processing industries. These by-products gained interest lately, in the context of food waste prevention and growing population number. In the tomato processing industry approximately, 8.5 million tons of wastes are generated globally, each year. The present study highlights the valuable bioactive constituents as lycopene, beta-carotene, glutamic acid or aspartic acid from the by-products of tomato processing industries, which can be revalorized as incorporated nutrients in functional foods. Tomato consumption is directly associated with the prevention of different chronic diseases and carcinogenesis, however the carotenoids bioavailability is a key factor in this process. Further, fiber content together with protein content of tomato seeds and benefits of their consumption are emphasized. Value-added food products obtained by tomato peels or seeds addition are exemplified in this review (bakery, meat products, pasta and noodles, dairy and oil products as well as jams and functional ice cream), in order to embrace next prototypes that can transform vegetal by-products in functional nutrients.


Assuntos
Carotenoides/análise , Fibras na Dieta/análise , Manipulação de Alimentos/métodos , Lycopersicon esculentum/química , Proteínas de Vegetais Comestíveis/análise , Aminoácidos/análise , Disponibilidade Biológica , Carotenoides/farmacocinética , Alimento Funcional , Humanos , Sementes/química
11.
Molecules ; 23(9)2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30200192

RESUMO

Based on in silico results, recently we have assumed that FSCPX, an irreversible A1 adenosine receptor antagonist, inhibits the action of NBTI that is apparent on E/c curves of adenosine receptor agonists. As a mechanism for this unexpected effect, we hypothesized that FSCPX might modify the equilibrative and NBTI-sensitive nucleoside transporter (ENT1) in a way that allows ENT1 to transport adenosine but impedes NBTI to inhibit this transport. This assumption implies that our method developed to estimate receptor reserve for agonists with short half-life such as adenosine, in its original form, overestimates the receptor reserve. In this study, therefore, our goals were to experimentally test our assumption on this effect of FSCPX, to improve our receptor reserve-estimating method and then to compare the original and improved forms of this method. Thus, we improved our method and assessed the receptor reserve for the direct negative inotropic effect of adenosine with both forms of this method in guinea pig atria. We have found that FSCPX inhibits the effects of NBTI that are mediated by increasing the interstitial concentration of adenosine of endogenous (but not exogenous) origin. As a mechanism for this action of FSCPX, inhibition of enzymes participating in the interstitial adenosine production can be hypothesized, while modification of ENT1 can be excluded. Furthermore, we have shown that, in comparison with the improved form, the original version of our method overestimates receptor reserve but only to a small extent. Nevertheless, use of the improved form is recommended in the future.


Assuntos
Antagonistas do Receptor A1 de Adenosina/farmacologia , Adenosina/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Receptor A1 de Adenosina/metabolismo , Tioinosina/análogos & derivados , Xantinas/farmacologia , Antagonistas do Receptor A1 de Adenosina/química , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Cobaias , Tioinosina/farmacologia , Xantinas/química
12.
J Environ Radioact ; 192: 267-278, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29990774

RESUMO

In order to estimate the annual dose that the public receive from natural radioactivity, the identification of the potential risk areas is required which, in turn, necessitates understanding the relationship between the spatial distribution of natural radioactivity and the geogenic risk factors (e.g., rock types, presence of dikes, faults, physical conditions of soil, etc.). A detailed spatial analysis of outdoor ambient gamma dose equivalent rate was performed in the western side of Velence Hills, the largest outcropped granitic area in Hungary. In order to assess the role of local geology in the spatial distribution of gamma dose rates, field measurements were carried out at ground level at 300 sites along a 250 m x 250 m regular grid in a total surface of 19.8 km2. Digital image processing methods were applied to identify anomalies, heterogeneities and spatial patterns in the measured gamma dose rates, including local maxima and minima determination, digital cross sections, gradient magnitude and gradient direction, second derivative profile curvature, local variability, lineament density, 2D autocorrelation and directional variogram analyses. Statistical inference shows that different gamma dose rate levels are associated with the geological formations, with the highest level on the Carboniferous granite including outlying values. Moreover, digital image processing reveales that linear gamma dose rate spatial features are parallel to the SW-NE dike system and to the NW-SE main fractures. The results of this study underline the importance of understanding the role of geogenic risk factors influencing the ambient gamma dose equivalent rate received by public. The study also demonstrates the power of the image processing techniques for the identification of spatial pattern in field-measured geogenic radiation.


Assuntos
Raios gama , Monitoramento de Radiação/métodos , Poluentes Radioativos do Solo/análise , Radiação de Fundo , Geologia , Hungria , Processamento de Imagem Assistida por Computador , Doses de Radiação , Radioatividade , Análise Espacial
13.
Int J Mol Sci ; 19(3)2018 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-29534453

RESUMO

Fenugreek is a common herb possessing several bioactive components including diosgenin. Here, dietary fenugreek seed flour and diosgenin were evaluated on a model of endothelium-dependent vasorelaxation by abdominal aortas isolated from rats receiving high-fat, high-sugar diet (HFHSD). 60 male Wistar rats were randomized into six groups: (i) negative control getting conventional rat feed regimen; (ii) positive control receiving HFHSD; (iii) a test group fed 2 g/kg bw/day fenugreek seed flour (containing 10 mg/kg bw/day diosgenin) + HFHSD; (iv) three test groups fed 1, 10 and 50 mg/kg bw/day diosgenin + HFHSD. Alimentary treatments were carried out for six weeks. The abdominal aortas were isolated, and 2 mm wide rings were sectioned off and mounted at a resting tension of 10 mN in organ baths containing Krebs solution (36 °C) exposed to 95% O2 and 5% CO2. After 60-min incubation, a norepinephrine concentration-response (E/c) curve was generated to determine their half-maximal effective concentration (EC50) value. After 60-min wash-out, a pre-contraction with norepinephrine EC50 was made, followed by an acetylcholine E/c curve. Plasma glutathione levels, glutathione-handling enzyme activities and blood antioxidant capacities were also determined. HFHSD significantly decreased the dilatory response to acetylcholine and increased plasma glutathione levels and these effects were significantly reversed by fenugreek seed flour, 10 and 50 mg/kg bw/day diosgenin. Both fenugreek and diosgenin treatments prevent HFHSD-induced endothelial dysfunction and redox changes. As fenugreek treatment was more effective at lower acetylcholine concentrations than diosgenin treatments, components of fenugreek other than diosgenin may contribute to the beneficial effects of dietary fenugreek seed flour.


Assuntos
Diosgenina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Vasodilatação , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Diosgenina/administração & dosagem , Diosgenina/uso terapêutico , Endotélio Vascular/fisiologia , Masculino , Síndrome Metabólica/prevenção & controle , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Trigonella
14.
Int J Mol Sci ; 19(3)2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29518003

RESUMO

In developed, developing and low-income countries alike, type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases, the severity of which is substantially a consequence of multiple organ complications that occur due to long-term progression of the disease before diagnosis and treatment. Despite enormous investment into the characterization of the disease, its long-term management remains problematic, with those afflicted enduring significant degradation in quality-of-life. Current research efforts into the etiology and pathogenesis of T2DM, are focused on defining aberrations in cellular physiology that result in development of insulin resistance and strategies for increasing insulin sensitivity, along with downstream effects on T2DM pathogenesis. Ongoing use of plant-derived naturally occurring materials to delay the onset of the disease or alleviate symptoms is viewed by clinicians as particularly desirable due to well-established efficacy and minimal toxicity of such preparations, along with generally lower per-patient costs, in comparison to many modern pharmaceuticals. A particularly attractive candidate in this respect, is fenugreek, a plant that has been used as a flavouring in human diet through recorded history. The present study assessed the insulin-sensitizing effect of fenugreek seeds in a cohort of human volunteers, and tested a hypothesis that melanin-concentrating hormone (MCH) acts as a critical determinant of this effect. A test of the hypothesis was undertaken using a hyperinsulinemic euglycemic glucose clamp approach to assess insulin sensitivity in response to oral administration of a fenugreek seed preparation to healthy subjects. Outcomes of these evaluations demonstrated significant improvement in glucose tolerance, especially in patients with impaired glucose responses. Outcome data further suggested that fenugreek seed intake-mediated improvement in insulin sensitivity correlated with reduction in MCH levels.


Assuntos
Hipoglicemiantes/farmacologia , Hormônios Hipotalâmicos/sangue , Insulina/metabolismo , Melaninas/sangue , Hormônios Hipofisários/sangue , Extratos Vegetais/farmacologia , Trigonella/química , Adulto , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Sementes/química
15.
Eur J Med Chem ; 147: 266-278, 2018 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-29453094

RESUMO

3-(ß-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with Ki's < 10 µM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-ß-d-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(ß-d-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(ß-d-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low µM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Teoria Quântica , Triazóis/farmacologia , Células CACO-2 , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicogênio Fosforilase/metabolismo , Humanos , Cinética , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
16.
Molecules ; 22(10)2017 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-29048398

RESUMO

Reactions of O-peracylated C-(1-bromo-ß-d-glucopyranosyl)formamides with thioamides furnished the corresponding glucopyranosylidene-spiro-thiazolin-4-one. While O-debenzoylations under a variety of conditions resulted in decomposition, during O-deacetylations the addition of MeOH to the thiazolinone moiety was observed, and with EtOH and water similar adducts were isolated or detected. The structure and stereochemistry of the new compounds were established by means of NMR and electronic circular dichroism (ECD) data supported by time-dependent density functional theory ECD (TDDFT-ECD) calculations. TDDFT-ECD calculations could efficiently distinguish the proposed epimeric products having different absolute configuration in the spiro heterocyclic ring.


Assuntos
Monossacarídeos/química , Tiazolidinas/química , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
17.
J Med Chem ; 60(22): 9251-9262, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-28925695

RESUMO

Aryl substituted 1-(ß-d-glucosaminyl)-1,2,3-triazoles as well as C-ß-d-glucosaminyl 1,2,4-triazoles and imidazoles were synthesized and tested as inhibitors against muscle and liver isoforms of glycogen phosphorylase (GP). While the N-ß-d-glucosaminyl 1,2,3-triazoles showed weak or no inhibition, the C-ß-d-glucosaminyl derivatives had potent activity, and the best inhibitor was the 2-(ß-d-glucosaminyl)-4(5)-(2-naphthyl)-imidazole with a Ki value of 143 nM against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb inhibitor complexes revealed structural features of the strong binding and offered an explanation for the differences in inhibitory potency between glucosyl and glucosaminyl derivatives and also for the differences between imidazole and 1,2,4-triazole analogues.


Assuntos
Glucosamina/análogos & derivados , Glicogênio Fosforilase/antagonistas & inibidores , Imidazóis/farmacologia , Triazóis/farmacologia , Animais , Cristalografia por Raios X , Glucosamina/síntese química , Glucosamina/farmacologia , Humanos , Ligações de Hidrogênio , Imidazóis/síntese química , Cinética , Fígado/enzimologia , Músculo Esquelético/enzimologia , Domínios Proteicos , Coelhos , Relação Estrutura-Atividade , Triazóis/síntese química
18.
Molecules ; 22(5)2017 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-28534854

RESUMO

The term receptor reserve, first introduced and used in the traditional receptor theory, is an integrative measure of response-inducing ability of the interaction between an agonist and a receptor system (consisting of a receptor and its downstream signaling). The underlying phenomenon, i.e., stimulation of a submaximal fraction of receptors can apparently elicit the maximal effect (in certain cases), provides an opportunity to assess the receptor reserve. However, determining receptor reserve is challenging for agonists with short half-lives, such as adenosine. Although adenosine metabolism can be inhibited several ways (in order to prevent the rapid elimination of adenosine administered to construct concentration-effect (E/c) curves for the determination), the consequent accumulation of endogenous adenosine biases the results. To address this problem, we previously proposed a method, by means of which this bias can be mathematically corrected (utilizing a traditional receptor theory-independent approach). In the present investigation, we have offered in silico validation of this method by simulating E/c curves with the use of the operational model of agonism and then by evaluating them using our method. We have found that our method is suitable to reliably assess the receptor reserve for adenosine in our recently published experimental setting, suggesting that it may be capable for a qualitative determination of receptor reserve for rapidly eliminating agonists in general. In addition, we have disclosed a possible interference between FSCPX (8-cyclopentyl-N³-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N¹-propylxanthine), an irreversible A1 adenosine receptor antagonist, and NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, i.e., FSCPX may blunt the effect of NBTI.


Assuntos
Adenosina/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Modelos Estatísticos , Miócitos Cardíacos/metabolismo , Receptor A1 de Adenosina/metabolismo , Adenosina/farmacologia , Animais , Transporte Biológico , Simulação por Computador , Transportador Equilibrativo 1 de Nucleosídeo/agonistas , Cobaias , Meia-Vida , Cinética , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Antagonistas de Receptores Purinérgicos P1/farmacologia , Tioinosina/análogos & derivados , Tioinosina/farmacologia , Xantinas/farmacologia
19.
PLoS One ; 12(2): e0171520, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28166301

RESUMO

BACKGROUND: Cryopreservation of zebrafish embryos is still an unsolved problem despite market demand and massive efforts to preserve genetic variation among numerous existing lines. Chilled storage of embryos might be a step towards developing successful cryopreservation, but no methods to date have worked. METHODS: In the present study, we applied a novel strategy to improve the chilling tolerance of zebrafish embryos by introducing a preconditioning hydrostatic pressure treatment to the embryos. In our experiments, 26-somites and Prim-5 stage zebrafish embryos were chilled at 0°C for 24 hours after preconditioning. Embryo survival rate, ability to reach maturation and fertilizing capacity were tested. RESULTS: Our results indicate that applied preconditioning technology made it possible for the chilled embryos to develop normally until maturity, and to produce healthy offspring as normal, thus passing on their genetic material successfully. Treated embryos had a significantly higher survival and better developmental rate, moreover the treated group had a higher ratio of normal morphology during continued development. While all controls from chilled embryos died by 30 day-post-fertilization, the treated group reached maturity (~90-120 days) and were able to reproduce, resulting in offspring in expected quantity and quality. CONCLUSIONS: Based on our results, we conclude that the preconditioning technology represents a significant improvement in zebrafish embryo chilling tolerance, thus enabling a long-time survival. Furthermore, as embryonic development is arrested during chilled storage this technology also provides a solution to synchronize or delay the development.


Assuntos
Adaptação Biológica , Temperatura Baixa , Embrião não Mamífero , Peixe-Zebra , Animais , Sobrevivência Celular , Criopreservação/métodos , Crioprotetores , Embrião não Mamífero/efeitos dos fármacos , Fertilidade , Pressão Hidrostática
20.
J Environ Radioact ; 166(Pt 2): 309-320, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27491859

RESUMO

A detailed ambient gamma dose equivalent rate mapping based on field measurements at ground level and at 1 m height was carried out at 142 sites in 80 × 90 km area in Pest County, Hungary. Detailed digital image processing analysis was carried out to identify and characterise spatial features such as outlying points, anomalous zones and linear edges in a smoothed TIN interpolated surface. The applied method proceeds from the simple shaded relief model and digital cross-sections to the more complex gradient magnitude and gradient direction maps, 2nd derivative profile curvature map, relief map and lineament density map. Each map is analysed for statistical characteristics and histogram-based image segmentation is used to delineate areas homogeneous with respect to the parameter values in these maps. Assessment of spatial anisotropy is implemented by 2D autocorrelogram and directional variogram analyses. The identified spatial features are related to underlying geological and tectonic conditions using GIS technology. Results show that detailed digital image processing is efficient in revealing the pattern present in field-measured ambient gamma dose equivalent rates and they are related to regional scale tectonic zones and surface sedimentary lithological conditions in the study area.


Assuntos
Radiação de Fundo , Raios gama , Doses de Radiação , Monitoramento de Radiação/métodos , Sistemas de Informação Geográfica , Hungria , Processamento de Imagem Assistida por Computador , Análise Espacial
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