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1.
Molecules ; 27(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36234741

RESUMO

Hybrids 1,4-quinone with quinoline were obtained by connecting two active structures through an oxygen atom. This strategy allows to obtain new compounds with a high biological activity and suitable bioavailability. Newly synthesized compounds were characterized by various spectroscopic methods. The enzymatic assay used showed that these compounds were a suitable DT-diaphorase (NQO1) substrates as evidenced by increasing enzymatic conversion rates relative to that of streptonigrin. Hybrids were tested in vitro against a panel of human cell lines including melanoma, breast, and lung cancers. They showed also a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activity of the studied hybrids was increasing against the cell lines with higher NQO1 protein level, such as breast (MCF-7 and T47D) and lung (A549) cancers. Selected hybrids were tested for the transcriptional activity of the gene encoding a proliferation marker (H3 histone), cell cycle regulators (p53 and p21) and the apoptosis pathway (BCL-2 and BAX). The molecular docking was used to examine the probable interaction between the hybrids and NQO1 protein.


Assuntos
Antineoplásicos , Hidroxiquinolinas , Quinolinas , Antineoplásicos/química , Apoptose , Benzoquinonas , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Histonas , Humanos , Hidroxiquinolinas/farmacologia , Simulação de Acoplamento Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxigênio/metabolismo , Quinolinas/química , Quinonas/metabolismo , Quinonas/farmacologia , Estreptonigrina , Proteína Supressora de Tumor p53 , Proteína X Associada a bcl-2/metabolismo
2.
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
3.
Molecules ; 26(24)2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34946569

RESUMO

The recommended pharmacological therapy for patients with coronary artery disease (CAD) treated by coronary artery bypass grafting (CABG) is acetylsalicylic acid (ASA). To improve the antiplatelet effect, supplementation with flavonoids is also recommended. The aim of this study was to estimate anti-aggregation properties of diosmin, in combination with ASA, pre- and postoperatively and assess the relationship of this therapy with inflammatory processes in CAD patients undergoing CABG. The study patients (n = 26) took diosmin (1000 mg/day); the control patients (n = 27) took a placebo. The therapeutic period for taking diosmin was from at least 30 days before to 30 days after CABG. All patients also took 75 mg/day ASA. Platelet aggregation and IL-6, CRP, and fibrinogen concentrations were determined before and 30 days after surgery. Results showed that diosmin did not enhance the anti-aggregation effect of ASA at any assessment time. However, there was a stronger anti-aggregation effect 30 days after surgery that was diosmin independent and was associated with acute-phase markers in the postoperative period. Increased levels of inflammatory markers in the late phase of the postoperative period may provide an unfavorable prognostic factor in long-term follow-up, which should prompt the use of stronger antiplatelet therapy in patients after CABG.


Assuntos
Aspirina/farmacologia , Ponte de Artéria Coronária , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/cirurgia , Flavonoides/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Idoso , Aspirina/administração & dosagem , Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Doença da Artéria Coronariana/sangue , Suplementos Nutricionais , Feminino , Flavonoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Testes de Função Plaquetária
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
J Strength Cond Res ; 30(9): 2648-55, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26808860

RESUMO

Jastrzebska, M, Kaczmarczyk, M, and Jastrzebski, Z. Effect of vitamin D supplementation on training adaptation in well-trained soccer players. J Strength Cond Res 30(9): 2648-2655, 2016-There is growing body of evidence implying that vitamin D may be associated with athletic performance, however, studies examining the effects of vitamin D on athletic performance are inconsistent. Moreover, very little literature exists about the vitamin D and training efficiency or adaptation, especially in high-level, well-trained athletes. The purpose of the current study was to investigate the effect of vitamin D supplementation on training adaptation in well-trained football players. The subjects were divided into 2 groups: the placebo group (PG) and the experimental group (SG, supplemented with vitamin D, 5,000 IU per day). Both groups were subjected to High Intensity Interval Training Program. The selection to the groups was based on peak power results attained before the experiment and position on the field. Blood samples for vitamin D level were taken from the players. In addition, total work, 5, 10, 20, and 30 m running speed, squat jump, and countermovement jump height were determined. There were no significant differences between SG and PG groups for any power-related characteristics at baseline. All power-related variables, except the 30 m sprint running time, improved significantly in response to interval training. However, the mean change scores (the differences between posttraining and pretraining values) did not differ significantly between SG and PG groups. In conclusion, an 8-week vitamin D supplementation in highly trained football players was not beneficial in terms of response to High Intensity Interval Training. Given the current level of evidence, the recommendation to use vitamin D supplements in all athletes to improve performance or training gains would be premature. To avoid a seasonal decrease in 25(OH)D level or to obtain optimal vitamin D levels, the combination of higher dietary intake and vitamin D supplementation may be necessary.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Desempenho Atlético/fisiologia , Força Muscular/efeitos dos fármacos , Corrida/fisiologia , Futebol/fisiologia , Vitamina D/farmacologia , Adulto , Suplementos Nutricionais , Método Duplo-Cego , Teste de Esforço , Feminino , Humanos , Masculino , Músculo Esquelético/fisiologia , Vitamina D/sangue
11.
Molecules ; 21(2): 156, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26828467

RESUMO

A series of 5,8-quinolinedione derivatives containing one or two alkoxy groups was synthesized and characterized by ¹H- and (13)C-NMR, IR and MS spectra. X-ray diffraction was used to investigate the crystal structures of 6-chloro-7-(2-cyjanoethoxy)-5,8-quinolinedione and 6,7-di(2,2,2-trifloroethoxy)-5,8-quinolinedione. All studied compounds were tested in vitro for their antiproliferative activity against three human cancer cell lines and human normal fibroblasts. Most of the compounds showed higher cytotoxicity than the starting compound, 6,7-dichloro-5,8-quinolinedione, and cisplatin, which was used as a reference agent.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Quinolinas/química , Relação Estrutura-Atividade
12.
Molecules ; 18(4): 4526-43, 2013 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-23595090

RESUMO

A new series of betulin derivatives containing one or two pharmacophores bearing an acetylenic and carbonyl function at the C-3 and/or C-28 positions has been synthesized and characterized by ¹H- and ¹³C-NMR, IR, MS and elemental analyses. The crystal structure of 28-O-propynoylbetulin was determined by X-ray structural analysis. All new compounds, as well as betulin, were tested in vitro for their antiproliferative activity against human SW707 colorectal, CCRF/CEM leukemia, T47D breast cancer, and against murine P388 leukemia and Balb3T3 normal fibroblasts cell lines. Most of the compounds showed better cytotoxicity than betulin and cisplatin used as reference agent. 28-O-Propynoylbetulin was the most potent derivative, being over 500 times more potent than betulin and about 100 times more cytotoxic than cisplatin against the human leukemia (CCRF/CEM) cell line, with an ID50 value of 0.02 µg/mL.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Triterpenos/síntese química , Triterpenos/farmacologia , Animais , Células 3T3 BALB , Linhagem Celular Tumoral , Humanos , Leucemia P388 , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
13.
Postepy Hig Med Dosw (Online) ; 66: 696-701, 2012 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-23175323

RESUMO

INTRODUCTION: Folic acid (FA) may delay the formation of atherosclerotic lesions. Increased plasma levels of von Willebrand factor (VWF) are observed in cardiovascular disease, which leads to higher risk of thrombosis. Fibrinogen (Fb) is a well-documented risk factor of cardiovascular disease. The aim of this study was to analyze the effect of FA supplementation on the Fb, VWF and C-reactive protein (CRP) plasma concentrations in subjects with atherosclerosis risk factors. MATERIAL/METHODS: The study enrolled 124 Caucasian individuals (60 M, 64 F) with atherosclerosis risk factors--family history of premature ischaemic stroke, arterial hypertension, dyslipidaemia, overweight and obesity, cigarette smoking and low physical activity. The participants were asked to take FA in the low dose of 0.4 mg/24 h for three months. RESULTS: After FA supplementation a significant reduction of the VWF concentrations in females (76.6 vs 72.3%; p=0.028) and in males (75.5 vs 66.9%; p=0.001) was observed. Among women and men with dyslipidaemia concentrations of VWF decreased after FA supplementation (76.8% vs 69.6%; p=0.003 and 76.7% vs 67.8%; p=0.001 respectively). Among females and males with BMI ≥25 kg/m² concentrations of VWF decreased only in men (77.6% vs 66.5%; p=0.001). In female and male smokers supplementation of FA decreased VWF concentrations (82.5% vs 74.4%; p=0.012 and 76.6% vs 69.5%; p=0.036 respectively). DISCUSSION: The results of our study suggest that there is an effect of FA supplementation on VWF concentrations in subjects with atherosclerosis risk factors.


Assuntos
Aterosclerose/dietoterapia , Aterosclerose/metabolismo , Fatores de Coagulação Sanguínea/metabolismo , Proteína C-Reativa/metabolismo , Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Adulto , Comorbidade , Dislipidemias/sangue , Dislipidemias/epidemiologia , Feminino , Fibrinogênio/metabolismo , Humanos , Masculino , Obesidade/sangue , Obesidade/epidemiologia , Fatores de Risco , Fumar/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Adulto Jovem , Fator de von Willebrand/metabolismo
14.
Klin Oczna ; 114(1): 71-4, 2012.
Artigo em Polonês | MEDLINE | ID: mdl-22783751

RESUMO

Atomic force microscopy (AFM) allows to examine surface of different biological objects in the nearly physiological conditions at the nanoscale. The purpose of this work is to present the history of introduction and the potential applications of the AFM in ophthalmology research and clinical practice. In 1986 Binnig built the AFM as a next generation of the scanning tunnelling microscope (STM). The functional principle of AFM is based on the measurement of the forces between atoms on the sample surface and the probe. As a result, the three-dimensional image of the surface with the resolution on the order of nanometres can be obtained. Yamamoto used as the first the AFM on a wide scale in ophthalmology. The first investigations used the AFM method to study structure of collagen fibres of the cornea and of the sclera. Our research involves the analysis of artificial intraocular lenses (IOLs). According to earlier investigations, e.g. Lombardo et al., the AFM was used to study only native IOLs. Contrary to the earlier investigations, we focused our measurements on lenses explanted from human eyes. The surface of such lenses is exposed to the influence of the intraocular aqueous environment, and to the related impacts of biochemical processes. We hereby present the preliminary results of our work in the form of AFM images depicting IOL surface at the nanoscale. The images allowed us to observe early stages of the dye deposit formation as well as local calcinosis. We believe that AFM is a very promising tool for studying the structure of IOL surface and that further observations will make it possible to explain the pathomechanism of artificial intraocular lens opacity formation.


Assuntos
Técnicas de Diagnóstico Oftalmológico/instrumentação , Implante de Lente Intraocular/instrumentação , Microscopia de Força Atômica , Oftalmologia/normas , Humanos , Propriedades de Superfície , Avaliação da Tecnologia Biomédica/métodos
15.
Pharmaceutics ; 15(1)2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36678664

RESUMO

Lipophilicity is one of the basic properties of a potential drug determining its solubility in non-polar solvents and, consequently, its ability to passively penetrate the cell membrane, as well as the occurrence of various pharmacokinetic processes, including adsorption, distribution, metabolism, excretion, and toxicity (ADMET). Heterocyclic compounds containing a nitrogen atom play a significant role in the search for new drugs. In this study, lipophilicity as well as other physicochemical, pharmacokinetic and toxicity properties affecting the bioavailability of the quinolone-1,4-quinone hybrids are presented. Lipophilicity was determined experimentally as well as theoretically using various computer programs. The tested compounds showed low values of experimental lipophilicity and its relationship with the type of 1,4-quinone moiety. Introduction of the nitrogen atom reduced the lipophilicity depending on the position at the 5,8-quinolinedione moiety. The bioavailability of the tested compounds was determined in silico using the ADMET parameters. The obtained parameters showed that most of the hybrids can be used orally and do not exhibit neurotoxic effects. Similarity analysis was used to examine the relationship between the ADMET parameters and experimental lipophilicity. The ability of hybrids to interact with biological targets was characterized by global reactivity descriptors. The molecular docking study showed that the hybrids can inhibit the BCL-2 protein.

16.
Biomolecules ; 12(2)2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35204755

RESUMO

An intraluminal thrombus (ILT), which accumulates large numbers of neutrophils, plays a key role in abdominal aortic aneurysm (AAA) pathogenesis. This study aimed to compare levels of selected neutrophil inflammatory mediators in thick and thin ILT, plus adjacent AAA walls, to determine whether levels depend on ILT thickness. Neutrophil mediator levels were analysed by enzyme-linked immunosorbent assays in thick and thin segments of ILT, plus adjacent aneurysm wall sections, taken from one aneurysm sac each from 36 AAA patients. In aneurysmal walls covered by thick ILT, neutrophil elastase and TNF-a levels were significantly higher, as were concentrations of IL-6, in thick ILT compared to thin layers. Positive correlations of NGAL, MPO, and neutrophil elastase were observed between thick ILT and the adjacent wall and thin ILT and the adjacent wall, suggesting that these mediators probably infiltrate thick AAA compartments as well as thin. These observations might support the idea that neutrophil mediators and inflammatory cytokines differentially accumulate in AAA tissues according to ILT thickness. The increased levels of neutrophil mediators within thicker AAA segments might suggest the existence of an intensified proinflammatory state that in turn presumably might preferentially weaken the AAA wall at that region.


Assuntos
Aneurisma da Aorta Abdominal , Trombose , Aneurisma da Aorta Abdominal/patologia , Humanos , Neutrófilos/patologia , Trombose/patologia
17.
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.

18.
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.


Assuntos
Clopidogrel/administração & dosagem , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/administração & dosagem , Idoso , Alelos , Cromatografia Líquida de Alta Pressão , Clopidogrel/farmacocinética , Clopidogrel/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Polimorfismo Genético , Estudos Prospectivos , Ticlopidina/análogos & derivados , Ticlopidina/farmacocinética
19.
Eur J Cardiovasc Prev Rehabil ; 17(6): 725-9, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20453653

RESUMO

BACKGROUND: Few studies focus on the progeny of stroke patients with respect to the occurrence of other potential risk factors. METHODS: The study group covered 60 males and 62 females whose parents had suffered premature ischemic stroke (PIS); the control group comprised of 41 males and 47 females whose parents had no history of premature vascular event (mean age: 28.4 and 27.1 years, respectively). Examination of both the groups consisted of evaluation of their diet, measurement of arterial blood pressure and body mass index (BMI). Moreover, blood test was carried out and concentration of biochemical stroke risk factors was determined. RESULTS: The adult progeny of parents with a history of PIS followed a deficient, unbalanced, and nonvaried diet. Their average blood pressure and BMI reached higher values, compared with the results obtained in the control group (125.7±16.06 vs. 122.64±10.83 mmHg; 24.27±3.98 vs. 22.54±2.69 kg/m, respectively; P<0.05). The same applies to average concentrations of the triglycerides 1.22±0.76 vs. 1.06±0.54 mmol/l; total cholesterol (5.34±1.16 vs. 4.82±0.89 mmol/l), low-density lipoprotein-cholesterol (2.95±0.97 vs. 2.52±0.73 mmol/l), total homocysteine (11.22±4.22 vs. 10.18±2.45 µmol/l), and fibrinogen (2.91±0.68 vs. 2.78±0.6 g/l) (P<0.05). CONCLUSION: Adult children of PIS sufferers show different stroke risk factor profiles than the control group. It may indicate a need for preventive activities for this group in the future. Family occurrence of stroke requires further detailed studies on a larger cohort of patients from risk group.


Assuntos
Isquemia Encefálica/prevenção & controle , Prevenção Primária , Acidente Vascular Cerebral/prevenção & controle , Adulto , Idade de Início , Análise de Variância , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , Estudos de Casos e Controles , Feminino , Fibrinogênio/análise , Predisposição Genética para Doença , Hereditariedade , Homocisteína/sangue , Humanos , Lipídeos/sangue , Modelos Logísticos , Masculino , Razão de Chances , Linhagem , Fenótipo , Projetos Piloto , Polônia/epidemiologia , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Adulto Jovem
20.
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.

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