Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 40
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Pharmaceutics ; 13(6)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071116

RESUMO

A key parameter in the design of new active compounds is lipophilicity, which influences the solubility and permeability through membranes. Lipophilicity affects the pharmacodynamic and toxicological profiles of compounds. These parameters can be determined experimentally or by using different calculation methods. The aim of the research was to determine the lipophilicity of betulin triazole derivatives with attached 1,4-quinone using thin layer chromatography in a reverse phase system and a computer program to calculate its theoretical model. The physiochemical and pharmacokinetic properties were also determined by computer programs. For all obtained parameters, the similarity analysis and multilinear regression were determined. The analyses showed that there is a relationship between structure and properties under study. The molecular docking study showed that betulin triazole derivatives with attached 1,4-quinone could inhibit selected SARS-CoV-2 proteins. The MLR regression showed that there is a correlation between affinity scoring values (ΔG) and the physicochemical properties of the tested compounds.

2.
Molecules ; 26(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572631

RESUMO

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 µM, and, for 7b, they were 0.76 and 0.8 µM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Fosfatos/química , Triterpenos/química , Triterpenos/farmacologia , Linhagem Celular Tumoral , Humanos , Conformação Molecular
3.
Pharmacol Rep ; 73(2): 583-593, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33270185

RESUMO

BACKGROUND AND OBJECTIVE: Clopidogrel is frequently used as part of optimal dual antiplatelet therapy in high-bleeding risk patients with the acute coronary syndrome. The concentration of the inactive carboxylic acid metabolite of clopidogrel might be useful to evaluate the response to clopidogrel therapy. Therefore, we sought to correlate the inhibition of platelet aggregation with the plasma level of the inactive metabolite of clopidogrel in patients after percutaneous coronary interventions (PCI) and their associations with the most frequently studied genetic polymorphisms. For this purpose, the fast and simple HPLC method for determining the concentration of the inactive metabolite was developed. METHODS: The effect of CYP2C19, CYP3A4/5, ABCB1 and PON1 genes on the plasma inactive metabolite concentration of clopidogrel and the platelet aggregation was investigated in 155 patients before and after PCI. RESULTS: The concentration of the inactive metabolite of clopidogrel was not significantly different in the intermediate metabolizers (IM) of CYP2C19 compared with extensive metabolizers (EM) both before and after PCI, while inhibition of platelet aggregation was found to be significantly better in EM than in IM. The presence of the A allele at position 2677 in the ABCB1 gene was associated with a significantly lower concentration of inactive metabolite of clopidogrel before PCI. CONCLUSION: The CYP2C19*2 allele was associated with decreased platelet reactivity during clopidogrel therapy before and after PCI. Simultaneous determination of platelet aggregation and concentration of the inactive clopidogrel metabolite may be useful in clinical practice to find the cause of adverse effects or insufficient treatment effect in patients chronically treated with clopidogrel.

4.
Bioorg Chem ; 106: 104478, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33272711

RESUMO

In this research, betulin derivatives were bonded to the 1,4-quinone fragment by triazole linker. Furthermore, the enzymatic assay used has shown that these compounds are a good DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. The anticancer activities of the hybrids were tested against a panel of human cell lines, like: melanoma, ovarian, breast, colon, and lung cancers. The structure-activity relationship showed that the activity depends on the type of 1,4-quinone moiety and the tumor cell lines used. It was also found that the anticancer effects were increasing against the cell line with higher NQO1 protein level, like: breast (T47D, MCF-7), colon (Caco-2), and lung (A549) cancers. The transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and apoptosis pathway (BCL-2 and BAX) for selected compounds were determined. The molecular docking study was carried out to examine the interaction between the hybrids and NQO1 enzyme. The computational simulation showed that the type of the 1,4-quinone moiety influences location of the compound in the active site of the enzyme. It is worth noting that the study of new hybrids of betulin as substrate for NQO1 protein may lead to new medical therapeutic applications in the future.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Quinonas/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Quinonas/química , Relação Estrutura-Atividade , Especificidade por Substrato , Triterpenos/síntese química , Triterpenos/química
5.
Materials (Basel) ; 13(18)2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32957729

RESUMO

An intraocular lens (IOL) is a synthetic, artificial lens placed inside the eye that replaces a natural lens that is surgically removed, usually as part of cataract surgery. The opacification of the artificial lens can be related to the formation of the sediments on its surface and could seriously impair vision. The physicochemical analysis was performed on an explanted hydrophilic IOL and compared to the unused one, considered as a reference IOL. The studies were carried out using surface sensitive techniques, which can contribute to a better understanding of the sedimentation process on hydrophilic IOLs' surfaces. The microscopic studies allowed us to determine the morphology of sediments observed on explanted IOL. The photoelectron spectroscopy measurements revealed the presence of organic and inorganic compounds at the lens surface. Mass spectroscopy measurements confirmed the chemical composition of deposits and allowed for chemical imaging of the IOL surface. Applied techniques allowed to obtain a new set of information approximating the origin of the sediments' formation on the surface of the hydrophilic IOLs after Descemet's stripping endothelial keratoplasty.

6.
Biomed Res Int ; 2020: 3192350, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32596295

RESUMO

Pregnancy predisposes to thrombotic hemostasis, reflected in the laboratory as, e.g., increased levels of D-Dimers and fibrinogen, but in physiological pregnancy, the risk of venous thrombosis does not increase. Risk may increase if gestational diabetes mellitus (GDM) or nicotinism coexists. Study aims were to determine reference values for D-Dimers and fibrinogen concentrations in each trimester of pregnancy, corrected for GDM and nicotinism. Subjects and Methods. The study involved 71 pregnant women aged 25-44 y. Venous blood was collected three times: in the first (11-14 weeks), second (20-22 weeks), and third (30-31 weeks) trimesters. D-Dimer concentrations were determined by an enzyme-linked fluorescence assay, fibrinogen concentrations by a coagulation method according to Clauss. Results. Significant increases in D-Dimers and fibrinogen concentrations were observed, increasing with successive trimesters (p ANOVA < 0.0001). Furthermore, a positive correlation between D-Dimers and fibrinogen was detected in the second trimester of pregnancy (r = 0.475; p < 0.0001). In addition, a significantly higher fibrinogen concentration was found in women with GDM compared to without GDM (p = 0.0449). Reference ranges for D-Dimers were established, in trimester order, as follows: 167-721 ng/mL, 298-1653 ng/mL, and 483-2256 ng/mL. After adjusting for risk factors, significantly higher D-Dimer values (mainly second and third trimesters) were obtained: 165-638 ng/mL, 282-3474 ng/mL, and 483-4486 ng/mL, respectively. Reference ranges for fibrinogen were, in trimester order, 2.60-6.56 g/L, 3.40-8.53 g/L, and 3.63-9.14 g/L and, after adjustment for risk factors, 3.34-6.73 g/L, 3.40-8.84 g/L, and 3.12-9.91 g/L. Conclusions. We conclude that the increase in D-Dimers and fibrinogen levels in women with physiological pregnancy was compounded by gestational diabetes (GDM) and nicotinism. Therefore, D-Dimers and fibrinogen pregnancy reference values require correction for these risk factors.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Gravidez/sangue , Gravidez/estatística & dados numéricos , Adulto , Diabetes Gestacional/sangue , Diabetes Gestacional/epidemiologia , Feminino , Humanos , Projetos Piloto , Valores de Referência , Fatores de Risco , Fumar
7.
Spectrochim Acta A Mol Biomol Spectrosc ; 230: 118038, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31945713

RESUMO

Depending on temperature, the 2-amino-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-dione forms two polymorphic structures, which differ in the spatial arrangement of the amine group. Both polymorphs were investigated using different experimental methods as well as various quantum chemical calculations in order to characterise their molecular structures. We used X-ray diffraction, FT-IR and NMR (solid-state and liquid) methods supplemented by the density functional theory (DFT) calculations, molecular electrostatic potential (MEP) and molecular orbital (HOMO, LUMO) analyses. It was found that the arrangement of the amine group affected the crystal structure, formation of H-bonds, the amine and carbonyl vibration bands in the FT-IR spectra, chemical shift of amine group in 15N CP/MAS NMR and chemical shift of amine protons in 1H NMR spectra. Both polymorphs were tested on anticancer activity against a panel of human cancer cell lines. Comparing the activity of both compounds showed that activity against MCF-7, MDA-MB-231 and Caco-2 lines depend on the arrangement of the amine group. Moreover, both polymorphs exhibited the highest activity against cell line with high NQO1 protein level, such as: A549, MCF-7 and Caco-2. The molecular docking was used to examine the probable interaction between the ligand of the tested polymorphs and the NQO1 enzyme. The analysis showed that ligands formed a hydrophobic interaction with tryptophan (Trp105), phenylalanine (Phe126 and Phe178) and tyrosine (Tyr 126).


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias/tratamento farmacológico , Quinolinas/química , Cristalografia por Raios X , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/química , Neoplasias/patologia , Células Tumorais Cultivadas
8.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640137

RESUMO

Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3',3'-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 µM and 0.03 µM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.


Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Compostos Organofosforados/síntese química , Succinatos/química , Triterpenos/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Linhagem Celular , HIV-1/metabolismo , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
9.
Thromb Res ; 182: 79-88, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473402

RESUMO

In this paper we tested a group of 66 healthy volunteers in terms of the influence of circadian rhythm on selected parameters of the coagulation system and fibrinolytic system. Blood was collected at 6-hour intervals, at 8 am, 2 pm, 8 pm and 2 am. Circadian variability was observed in the coagulation system parameters as well as in the fibrinolytic system. We observed increased platelet aggregation, APTT prolongation, along with increased levels of factors (fibrinogen, PAI-1) and PAP and TAT complexes that influence coagulation and fibrinolysis systems, in the blood samples collected in the morning (8 am). We also demonstrated a circadian rhythm in the number of circulating platelets (PLT), with a peak in the afternoon (2 pm) accompanied by increased concentrations of t-PA, D-dimers and PT prolongation. Based on the obtained results it was possible to conclude that circadian rhythm had an influence on the activation of coagulation processes in the morning, with a progressive activation of fibrinolysis up to the afternoon. Our results may be helpful in determining the transient risk of cardiovascular events, including myocardial infarction and ischemic stroke, and hence, can contribute to the effective prevention of such events. Such observations may also become a starting point of departure for further studies aimed at determining the circadian effect of secretion of parameters in the hemostasis system on the other systems and parameters in the human body.


Assuntos
Ritmo Circadiano , Hemostasia , Adulto , Coagulação Sanguínea , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Fibrinólise , Voluntários Saudáveis , Humanos , Masculino , Melatonina/sangue , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Agregação Plaquetária , Adulto Jovem
10.
Eur J Med Chem ; 177: 302-315, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158746

RESUMO

Betulin-1,4-quinone hybrids were obtain by connecting two active structures with a linker. This strategy allows for obtaining compounds showing a high biological activity and better bioavailability. In this research, synthesis, anticancer activity and molecular docking study of betulin-1,4-quinone hybrids are presented. Newly synthesized compounds were characterized by 1H, 13C NMR, IR and HR-MS. Hybrids were tested in vitro against a panel of human cell lines including glioblastoma, melanoma, breast and lung cancer. They showed a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activities of the studied hybrids were increasing against the cell line with higher NQO1 protein level, like melanoma (C-32), breast (MCF-7) and lung (A-549) cancer. Selected hybrids were tested on the transcriptional activity of the gene encoding a proliferation marker (H3 histone), a cell cycle regulators (p53 and p21) and an apoptosis pathway (BCL-2 and BAX). The obtained results suggested that the tested compounds caused a mitochondrial apoptosis pathway in A549 and MCF-7 cell lines. The molecular docking was used to examine the probable interaction between the hybrids and human NAD[P]H-quinone oxidoreductase (NQO1) protein. The computational studies showed that the type of the 1,4-quinone moiety affected the location of the compound in the active site of the enzyme. Moreover, it was shown that an interaction of 1,4-quinone fragment with the hydrophobic matrix of the active site near Tyr128, Phe178, Trp105 and FAD cofactor could explain the observed increase of TP53 gene expression.


Assuntos
Antineoplásicos/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Quinonas/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Betula/química , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/química , Ligação Proteica , Quinonas/síntese química , Quinonas/química , Quinonas/metabolismo , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/metabolismo , Proteína Supressora de Tumor p53/genética
11.
Exp Eye Res ; 181: 178-184, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30735658

RESUMO

The purpose of the study was to investigate the endogenous fluorescence of the keratoconic cornea in order to analyze changes in the spectra due to the keratoconic stroma abnormalities. Twenty-two corneal buttons obtained from patients with keratoconus (KC, N = 22) at the time of penetrating keratoplasty were used. As a reference, twelve normal corneas (N = 12): ten from the Eye Bank and two from enucleated eyes due to choroidal melanoma were used. The fluorescence excitation/emission matrices (EEM) in the ranges of 250-400/260-600 nm were recorded. Healthy cornea, keratoconic cornea and sclera showed three main EEM bands, which correspond to the following fluorophores: tryptophan residues in the proteoglycan fraction of corneal/scleral stromas, naturally occurring collagen cross-links and the NAD(P)H fraction present in the metabolically active cells. Relative intensity factors S1, S2 and S3 describing the contribution of each kind of fluorophore to the total fluorescence of the tissue were calculated. Normal and keratoconic corneas show qualitatively similar fluorescence matrices, but the statistically significant differences in the mean values of the S1, S2 and S3 parameters for the KC and normal corneas were observed indicating changes in contribution of different fluorophores to the whole fluorescence of the tissue. Moreover, differences between multidimensional distribution of the relative intensity factors S1, S2 and S3 between these groups were demonstrated (p < 0.001). In conclusions: Differences in the relative intensity factors calculated on a basis of the fluorescence spectra can correspond to the changes found in the KC stroma regarding natural collagen cross-links and the proteoglycan fraction. These parameters well differentiate the KC and normal corneas that could serve as an additional tool for the keratoconus characterization.


Assuntos
Substância Própria/diagnóstico por imagem , Ceratocone/diagnóstico , Adulto , Substância Própria/cirurgia , Feminino , Fluorescência , Humanos , Ceratocone/cirurgia , Ceratoplastia Penetrante , Masculino , Pessoa de Meia-Idade , Espectrometria de Fluorescência , Adulto Jovem
12.
J Hum Kinet ; 61: 63-72, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29599860

RESUMO

There is no clear evidence that vitamin D effectively improves physical capacity in high-level athletes. The aim of this study was to confirm that vitamin D supplementation of soccer players during eight-week high-intensity training would have a significant effect on their aerobic capacity. The subjects were divided into two groups: the experimental one that was supplemented with vitamin D (SG, n = 20), and the placebo group (PG, n = 16), not supplemented with vitamin D. All the players were subjected to the same soccer training described as High-Intensity Interval Training (HIIT). The data of the vitamin D level, PWC170, lactate threshold (LT) were collected just before and after the intervention. A significant increase in vitamin D concentration (119%) was observed in the supplemented group, while the non-supplemented group showed a decrease of 8.4%. The studied subjects improved VO2max results by 20% in the SG, and by 13% in the PG. The improvement in velocity at the LT was similar in both groups. Results of this study show that vitamin D can have a positive, though moderate, effect on aerobic performance in players subjected to high-intensity training in the form of small-sided games for 8 weeks.

13.
J Vasc Surg ; 68(6S): 30S-37S, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29571624

RESUMO

BACKGROUND: The hemostatic system cooperates with proteolytic degradation in processes allowing abdominal aortic aneurysm (AAA) formation. In previous studies, it has been suggested that aneurysm rupture depends on intraluminal thrombus (ILT) thickness, which varies across each individual aneurysm. We hypothesized that hemostatic components differentially accumulate in AAA tissue in relation to ILT thickness. Thick (A1) and thin (B1) segments of ILTs and aneurysm wall sections A (adjacent to A1) and B (adjacent to B1) from one aneurysm sac were taken from 35 patients undergoing elective repair. METHODS: Factor levels were measured using enzyme-linked immunosorbent assay of protein extract. RESULTS: Tissue factor (TF) activities were significantly higher in thinner segments of AAA (B1 vs A1, P = .003; B vs A, P < .001; B vs A1, P < .001; B vs B1, P = .001). Significantly higher tissue plasminogen activator was found in thick thrombus-covered wall segments (A) than in B, A1, and B1 (P = .015, P < .001, and P < .001, respectively). Plasminogen concentrations were highest in ILT. Concentrations of α2-antiplasmin in thin ILT adjacent walls (B) were higher compared with wall (A) adjacent to thick ILT (P = .021) and thick ILT (A1; P < .001). Significant correlations between levels of different factors were mostly found in thick ILT (A1). However, no correlations were found at B sites, except for a correlation between plasmin and TF activities (r = 0.55; P = .004). CONCLUSIONS: These results suggest that higher TF activities are present in thinner AAA regions. These parameters and local fibrinolysis may be part of the processes leading to destruction of the aneurysm wall.


Assuntos
Aorta Abdominal/química , Aneurisma da Aorta Abdominal/sangue , Fibrinólise , Tromboplastina/análise , Trombose/sangue , Idoso , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/cirurgia , Aortografia/métodos , Angiografia por Tomografia Computadorizada , Dilatação Patológica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasminogênio/análise , Trombose/diagnóstico por imagem , Trombose/patologia , Trombose/cirurgia , Ativador de Plasminogênio Tecidual/análise , Remodelação Vascular , alfa 2-Antiplasmina/análise
14.
Biomed Res Int ; 2018: 3205324, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30643799

RESUMO

Homocysteine (Hcy) may affect the pathogenesis of abdominal aortic aneurysms (AAAs) through enhancement of proteolysis and an impaired coagulation/fibrinolysis system. Intensified haemostatic capacity may promote local proteolytic degradation of the aortic wall. This study aimed to examine the effects of Hcy on haemostatic and proteolytic processes in samples of thick and thin fragments of the ILT and underlying walls. Subjects and Methods. Thirty-six patients who underwent AAA surgery were enrolled. Aneurysm tissue sections were incubated with DL-Hcy (100 and 500 µmol/L) in a series of experiments and analyzed for concentration/activity of proteolytic and haemostatic markers by enzyme-linked immunosorbent assay. Results. Incubation of wall underlying thin ILT segments (B) with DL-Hcy resulted in an increase of active MMP-2 levels compared to control tissue (9.54 ± 5.88 versus 7.44 ± 4.48, p=0.011). DL-Hcy also induced t-PA and plasminogen concentration increases in thin thrombus sections (B1) compared to control tissue (respectively: 1.39 ± 1.65 versus 0.84 ± 0.74, p=0.024; 11.64 ± 5.05 versus 10.34 ± 5.52, p=0.018). In contrast, wall adjacent to thick thrombus segments (A) showed decreases in MMP-2 and TF activities compared to control (respectively, 5.89 ± 3.39 versus 7.26 ± 5.49, p=0.046; 67.13 ± 72.59 versus 114.46 ± 106.29, p=0.007). In thick ILT sections (A1), DL-Hcy decreased MMP-2 activity and t-PA and plasminogen concentrations compared to control tissue (respectively, 2.53 ± 2.02 versus 3.28 ± 2.65, p=0.006; 0.67 ± 0.57 versus 0.96 ± 0.91, p=0.021; 9.25 ± 4.59 versus 12.63 ± 9.56, p=0.017). In addition, analysis revealed positive correlations at all sites between activities/concentrations of MMP-2, TF, and PAI-1 measured in control tissues and after incubation with DL-Hcy. Conclusions. These data indicate the potential for excess Hcy to enhance damage of arterial wall in thinner AAA segments as a result of the increased activity of MMP-2 and fibrinolytic factors.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Fibrinólise , Homocisteína/metabolismo , Proteólise , Trombose/metabolismo , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/patologia , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Pessoa de Meia-Idade , Plasminogênio/metabolismo , Tromboplastina/metabolismo , Trombose/patologia , Ativador de Plasminogênio Tecidual/metabolismo
15.
Molecules ; 22(11)2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29104263

RESUMO

Betulin derivatives containing a 1,2,3-triazole ring possess a wide spectrum of biological activities, including antiviral, anticancer, and antibacterial activity. A series of novel triazoles were prepared by the 1,3-dipolar cycloaddition reaction between the alkyne derivatives of betulin and organic azides. The chemical structures of the obtained compounds were defined by ¹H and 13C NMR, IR, and high-resolution mass spectrometry (HR-MS) analysis. The target triazoles were screened for their antiviral activity against DNA and RNA viruses. The cytotoxic activity of the obtained compounds 5a-k and 6a-h was determined using five human cancer cell lines (T47D, MCF-7, SNB-19, Colo-829, and C-32) by a WST-1 assay. The bistriazole 6b displayed a promising IC50 value (0.05 µM) against the human ductal carcinoma T47D (500-fold higher potency than cisplatin). The microdilution method was applied for an evaluation of the antimicrobial activity of all of the compounds. The triazole 5e containing a 3'-deoxythymidine-5'-yl moiety exhibited antibacterial activity against two gram-negative bacteria vz. Klebsiellapneumoniae and Escherichia coli (minimal inhibitory concentration (MIC) range of 0.95-1.95 µM).


Assuntos
Triazóis/química , Triterpenos/química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/química , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
16.
Eur J Clin Pharmacol ; 73(9): 1085-1094, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28589365

RESUMO

BACKGROUND: Antiplatelet response to clopidogrel and its influence upon the risk of cardiovascular adverse events among patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI) has not been investigated fully. METHODS: Two hundred eleven patients treated with aspirin and clopidogrel were included in the study. Immediately before PCI, residual platelet reactivity testing with impedance aggregometry assay and a single-nucleotide polymorphism genotyping analysis targeting variants of CYP2C19, ABCB1, and PON1 genes was performed. After the index PCI, the patients were screened for cardiovascular events 6 months following bare-metal stent implantation or 12 months following drug-eluting stent implantation. RESULTS: High on-treatment platelet reactivity (HTPR) was observed in 19.43% individuals and low-TPR (LTPR) in 26.54%. In multivariate analysis, HTPR was significantly (p < 0.05) associated with a history of diabetes, higher systolic blood pressure, and platelet count comparing to that of other patients. LTPR was significantly associated with no history of hypertension, younger age, lower platelet count, absence of the CYP2C19*2 variant, and lower CRP plasma level. Overall, cardiac adverse events were noted in 14.23% patients. Survival analysis with the Cox proportional hazard model showed no influence of residual platelet reactivity during clopidogrel therapy upon both ischemic and hemorrhagic events. However, significant predictors for composite of major adverse cardiac events and hospitalization for cardiovascular causes were identified (the higher CCS class prior to coronary intervention and the higher creatinine serum concentration). CONCLUSIONS: The platelet response to clopidogrel has no impact upon post-procedural adverse events at mid-term follow-up in patients with stable CAD undergoing PCI. This finding suggests that routine platelet reactivity testing is not beneficial in this group of patients.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/cirurgia , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Plaquetas/efeitos dos fármacos , Clopidogrel , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Testes de Função Plaquetária , Polimorfismo Genético , Stents , Ticlopidina/efeitos adversos , Ticlopidina/farmacocinética , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico
17.
Eur J Med Chem ; 126: 969-982, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-28006669

RESUMO

The natural 7-amino-5,8-quinolinodione antibiotics were the substrate for the NQO1 protein. The structure-activity relationship showed that the 5,8-quinolinedione moiety was responsible for the interaction with the enzyme. In our research, we presented the synthesis, cytotoxic activity and theoretical study of a 5,8-quinolinedione compound as a potential inhibitor of the NQO1 enzyme. Mono and disubstituted alkynyloxy derivatives of the 5,8-quinolinedione were synthesized and characterized by 1H, 13C NMR, IR and HR-MS spectra. Newly synthesized derivatives were also tested for their biological activity in vitro against the human cancer cell lines. They showed high cytotoxic activity depending on the type of substituent and the employed tumor cell lines. Moreover, two breast cancer cell lines, MDA-MB-231 and MCF-7, were chosen for analysis as they are characterized by different NQO1 protein levels. It was found that cytotoxic activities of all studied compounds increased against the cell line with a higher NQO1 protein level. The molecular docking was used to examine the probable interaction between the molecules of alkynyloxy derivatives and human NAD[P]H-quinone oxidoreductase (NQO1) protein. The computational studies showed that the 5,8-quinolinedione moiety of all docked compounds was located deeply in the hydrophobic matrix of the active site near the side chains of aromatic residues in positions Trp 105, Phe 178, Tyr 126 and Tyr 128. In every case, introduction of aromatic moieties into the 5,8-quinolinedione molecule led to an increase in the binding affinity in relation to the 6,7-dichloro-5,8-quinolinedione.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Quinolinas/síntese química , Quinolinas/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , NAD(P)H Desidrogenase (Quinona)/química , NAD(P)H Desidrogenase (Quinona)/metabolismo , Conformação Proteica , Quinolinas/química , Quinolinas/metabolismo , Relação Estrutura-Atividade
18.
J Biomol Struct Dyn ; 35(3): 551-563, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26872619

RESUMO

Collagen fibrils type I display a typical banding pattern, so-called D-periodicity, of about 67 nm, when visualized by atomic force or electron microscopy imaging. Herein we report on a significant shortening of the D-period for human corneal collagen fibrils type I (21 ± 4 nm) upon air-drying, whereas no changes in the D-period were observed for human scleral collagen fibrils type I (64 ± 4 nm) measured under the same experimental conditions as the cornea. It was also found that for the corneal stroma fixed with glutaraldehyde and air-dried, the collagen fibrils show the commonly accepted D-period of 61 ± 8 nm. We used the atomic force microscopy method to image collagen fibrils type I present in the middle layers of human cornea and sclera. The water content in the cornea and sclera samples was varying in the range of .066-.085. Calculations of the D-period using the theoretical model of the fibril and the FFT approach allowed to reveal the possible molecular mechanism of the D-period shortening in the corneal collagen fibrils upon drying. It was found that both the decrease in the shift and the simultaneous reduction in the distance between tropocollagen molecules can be responsible for the experimentally observed effect. We also hypothesize that collagen type V, which co-assembles with collagen type I into heterotypic fibrils in cornea, could be involved in the observed shortening of the corneal D-period.


Assuntos
Colágeno Tipo I/química , Córnea , Adulto , Colágeno Tipo I/metabolismo , Colágeno Tipo I/ultraestrutura , Córnea/metabolismo , Feminino , Humanos , Masculino , Microscopia de Força Atômica , Pessoa de Meia-Idade , Conformação Proteica , Relação Estrutura-Atividade
19.
J Nutr Sci Vitaminol (Tokyo) ; 63(6): 357-364, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29332896

RESUMO

Vitamin D deficiency has been associated with increased risk for cardiovascular disease and anemia. Vitamin D-related changes in lipid profile have been studied extensively but the relationship between vitamin D and lipid metabolism is not completely understood. As both vitamin D and intermittent training may potentially affect iron and lipid metabolism, the aim of the study was to evaluate whether a daily supplementation of vitamin D can modulate the response of hematological and lipid parameters to high-intensity interval training (HIIT) in soccer players. Thirty-six young elite junior soccer players were included in the placebo-controlled, double-blind study. Participants were non-randomly allocated into either a supplemented group (SG, n=20, HIIT and 5,000 IU of vitamin D daily) or placebo group (PG, n=16, HIIT and sunflower oil). Hematological parameters were ascertained before and after the 8-wk training. The change score (post- and pre-training difference) was calculated for each individual and the mean change score (MCS) was compared between SG and PG using the t test and analysis of covariance. There were no differences between SG and PG at baseline. The red and white cell count, hemoglobin, hematocrit, MCHC, ferritin, and HDL-cholesterol changed significantly over the 8-wk HIIT. However, no significant differences in MCS were observed between SG and PG for any variable. A daily vitamin D supplement did not have any impact on alteration in hematological or lipid parameters in young soccer players in the course of high-intensity interval training.


Assuntos
Suplementos Nutricionais , Treinamento Intervalado de Alta Intensidade , Ferro/metabolismo , Lipídeos/sangue , Futebol , Vitamina D/administração & dosagem , Adolescente , Atletas , HDL-Colesterol/sangue , Método Duplo-Cego , Contagem de Eritrócitos , Índices de Eritrócitos , Hematócrito , Testes Hematológicos , Hemoglobinas/análise , Humanos , Contagem de Leucócitos , Placebos
20.
Int J Occup Med Environ Health ; 29(5): 801-14, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27518889

RESUMO

OBJECTIVES: The objective of the study was to reveal morphology, electrolyte and chosen biochemical parameters in terms of health risk in runners in reference to their age and running speed in the case of running a distance of 100 km, which occur after 12 h or 24 h of recovery. MATERIAL AND METHODS: Fourteen experienced, male, amateur, ultra-marathon runners, divided into two age and two speed groups took part in the 100-km run. Blood samples for analyses indexes were collected from the ulnar vein just before the run, after 25 km, 50 km, 75 km and 100 km, as well as 12 h and 24 h after termination of the run. RESULTS: The sustained ultramarathon run along with the distance covered (p < 0.05) caused an increase in myoglobin (max 90-fold), bilirubin (max 2.8-fold) and total antioxidant status (max 1.15-fold), which also continued during the recovery. Significant changes in the number of white blood cells were observed with each sequential course and could be associated with muscle damage. The electrolyte showed changes towards slight hyperkalemia, but no changes in natrium and calcium concentrations. There were no significant differences between the age and speed groups for all the parameters after completing the 100-km run as well as after 12 h and 24 h of recovery. CONCLUSIONS: Considering changes in blood morphology and chosen biochemical parameters in ultra-marathon runners during a 100-km run it can be stated that such an exhausting effort may be dangerous for human health due to metabolic changes and large damage to the organs. Negative metabolic changes are independent of age of an ultramarathon runner and occur both in younger (32±5.33 years) and older participants (50.56±9.7 years). It can be concluded that organ damage and negative metabolic changes during a 100-km run occur similarly in participants less experienced as well as in well trained runners. Int J Occup Med Environ Health 2016;29(5):801-814.


Assuntos
Antioxidantes/análise , Bilirrubina/sangue , Eletrólitos/sangue , Mioglobina/sangue , Esforço Físico/fisiologia , Corrida/fisiologia , Adulto , Fatores Etários , Atletas , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...