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1.
Artigo em Inglês | MEDLINE | ID: mdl-32365672

RESUMO

Background: The Roma population is one of the largest marginalized population groups in Europe. The aim of our work was to summarize the morbidity of lifestyle-related diseases and infectious diseases in the Roma population living in segregated settlements. Methods: We used data from the cross-sectional study HepaMeta, in which we examined 452 Roma subjects with an average age of 34.7 ± 9.1 years, 35.2% of which were men, and 403 non-Roma subjects with an average age of 33.5 ± 7.4 years, 45.9% of which were men. We collected data by means of a questionnaire, anthropometric measures, and we analyzed blood and urine samples. Results: Roma subjects had a higher incidence of metabolic syndrome (RR: 1.478 (1.159-1.885), p < 0.0001), obesity or waist circumference >94 cm in men/80 cm in women (RR: 1.287 (1.127-1.470), p < 0.0001), and HDL-C < 1.03 mmol/L in men or <1.29 in women (RR: 2.004 (1.730-2.321), p < 0.0001) than their non-Roma counterparts. Subjects of the Roma population were more frequently diagnosed with kidney disease (RR: 1.216 (1.096-1.349), p < 0.0001), HBsAg positivity (RR: 4.468 (2.373-8.415), p < 0.0001), anti HBc IgG positivity (RR: 3.13 (2.598-4.224), p < 0.0001), and anti HEV positivity (RR: 2.972 (1.226-7.287), p < 0.0001). Serological markers of Toxoplasma gondii infection and Toxocara spp. were observed much more frequently among Roma than non-Roma subjects (RR: 1.868 (1.520-2.296), p < 0.0001, for Toxoplasma gondii; and RR: 21.812 (8.097-58.761), p < 0.0001, for Toxocara spp.). Conclusions: Poor socio-economic conditions, an unhealthy lifestyle, and barriers precluding access to healthcare are factors that affect the Roma population in settlements and lead to an increased prevalence of metabolic syndrome and its components, kidney disease, viral hepatitis B and E, and some parasitic diseases.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32397342

RESUMO

Background: The aim of our work is to objectify the manner of transmission of HBV infection in young adult and middle-aged Roma people who live in the settlements. Methods: We used data from the cross-sectional study HepaMeta. We analyzed Roma people living in the settlements in East Slovakia, who have had HBsAg and anti HBc IgG antibodies examined. Results: We analyzed a cohort of 452 Roma participants with a mean of age 34.67 ± 9.14 years-159 (35.2%) were males. HBsAg positivity was diagnosed in 12.4% and the presence of anti HBc IgG antibodies was confirmed in 52% of participants. Prevalence of HBsAg positivity increases significantly with higher age, (p = 0.026), as well as the presence of anti HBc IgG antibodies (p < 0.0001). The prevalence of HBsAg positivity has doubled and anti HBc IgG positivity has tripled within two decades (<25 years vs. 35-45 years) in Roma settlements in East Slovakia. Conclusions: These findings allow us to express an opinion that horizontal transmission in adulthood may play an important role in the spreading of HBV infection.

3.
Cent Eur J Public Health ; 28(1): 70-73, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32228821

RESUMO

OBJECTIVE: Hepatitis E infection is one of the most frequent acute hepatitis in the world. Currently five human genotypes with different geographical distributions and distinct epidemiologic patterns are identified. In Slovakia, only rare cases of hepatitis E have been reported in recent years. Therefore, the aim of the study was to evaluate the prevalence of anti-HEV total antibodies and the main risk factors for HEV in the general population in Eastern Slovakia. METHODS: Detection of anti-HEV total antibodies samples was done by a commercial enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Of 175 hospitalized patients included in the study, 76 (43.5%) showed positivity for anti-HEV total antibodies. No statistically significant differences were found in anti-HEV positivity between men and women or in the groups of different living areas (town/village - urban/rural). CONCLUSION: Prevalence of anti-HEV total antibodies of hospitalised patients was high. The risk factor significantly associated with antibody positivity was eating raw meat. Other factors, such as sex, age, living area and contact with animals were not associated with antibody positivity.


Assuntos
Hepatite E/epidemiologia , Hospitalização/estatística & dados numéricos , Ensaio de Imunoadsorção Enzimática , Feminino , Anticorpos Anti-Hepatite/isolamento & purificação , Vírus da Hepatite E/imunologia , Humanos , Masculino , Fatores de Risco , Estudos Soroepidemiológicos , Eslováquia/epidemiologia
4.
J Appl Toxicol ; 40(1): 64-71, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31222780

RESUMO

Proflavine derivatives are extremely interesting chemotherapeutic agents, which have shown promising pharmaceutical potential due to their wide range of biological activities. This review summarizes the current state of research into the anticancer, antimicrobial, antimalarial and antileishmanial properties of these attractive compounds. Our attention has focused on new classes of proflavine conjugates, which display significant levels of anticancer activity. Highly promising cytotoxic properties have been identified in proflavine conjugates with imidazolidinones, ureas and thioureas. In particular, proflavine-dialkyldithioureas displayed substantial cytotoxic effect against the human leukemia HL-60 cells with IC50 values from 7.2 to 34.0 µm. As well, palladium complexes with proflavine ligand have important biologic activity. The LC50 values of these complexes were significantly lower than that of cisplatin against the SK-BR-3 cell line.

5.
Can J Gastroenterol Hepatol ; 2019: 3024630, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058108

RESUMO

Background and Aim. To develop a noninvasive magnetic resonance imaging (MRI) method for evaluation of liver fibrosis. We evaluate the utility of hepatocyte-phase Gadoxetate disodium-enhanced magnetic resonance (MR) imaging in staging hepatic fibrosis and compare it with histological analysis as the reference standard (liver biopsy). Methods. Prospective cohort of 78 patients, who received Gadoxetate disodium dynamic contrast-enhanced MRI (DCE-MRI), were divided into three groups. The first group (n=19) was a control group of healthy individuals without liver injury and remaining 59 subjects were chronic hepatitis B and C patients who underwent liver biopsy. These patients were divided into the mild fibrosis F1-F2 (n=32) and advanced fibrosis F3-F4 (n=27) groups. Patients were examined by generated DCE-MRI in 20th minute. Variables such as liver surface changes, homogeneities, and quantitative contrast liver/spleen ratio-Q-LSCR were evaluated and these results were consequently compared between the three groups. Results. Gd-EOB-DTPA contrast-enhanced dynamic liver MRI examination (DCE-MRI) can in the 20th minute differentiate mild stage of liver fibrosis (F1-F2) from severe stage of liver fibrosis (F3-F4) on the basis of liver surface changes, homogeneities, and quantitative contrast liver/spleen ratio-Q-LSCR. Diagnostic MRI criteria were created and named MRI Triple test. This test correctly identified 96% of patients with F3-F4 fibrosis and 91% of patients with the F1-F2 fibrosis in the liver biopsy. This test correctly identified 42,1% of patients in the control group (presumed F0 fibrosis without liver disease). Spearman's rank correlation coefficient (r = 0,86, P < .001) confirmed high agreement of biopsy and MR Triple test. MR Triple test's sensitivity was 96.30% (95%CI 81.03% to 99.91%), specificity 90.62% (95%CI 74.98% to 98.02%), positive predictive value 89.66% (95%CI 74.64% to 96.23%), and negative predictive value 96.67% (95%CI 80.86% to 99.50%) for discrimination between F3-4 and F1-2 fibrosis on liver biopsy. Conclusions. Gd-EOB-DTPA contrast-enhanced MRI liver examination in 20th minute is able to reliably differentiate mild stage of liver fibrosis (F1-F2) from severe stage fibrosis (F3-F4) on the basis of Triple test (liver surface changes, homogeneities, and quantitative contrast liver/spleen ratio-Q-LSCR).

6.
Can J Gastroenterol Hepatol ; 2018: 6095097, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30402450

RESUMO

Background and Aims: Chronic hepatitis C is a systemic disease and type 2 diabetes mellitus (T2DM) belongs to more common extrahepatic. The aim of this study was to (i) explore the prevalence of impaired fasting glucose (IFG) and T2DM in patients with chronic hepatitis C, (ii) explore the effect of direct acting antivirals (DAA) treatment on the glycemia, and (iii) explore the factors that modulate the effect of DAA treatment on glycemia in patients with chronic hepatitis C. Methods: We performed a longitudinal retrospective observational study focused on the patients undergoing DAA treatment of chronic hepatitis C. Data about glycemia, history of diabetes, hepatitis C virus, treatment, and liver status, including elastography, were obtained at baseline (before treatment start), at the end of treatment and 12 weeks after the end of treatment. Patients were treated with various regimens of direct acting antivirals. Results: We included 370 patients; 45.9% had F4 fibrosis. At baseline, the prevalence of T2DM increased with the degree of fibrosis (F0-F2 14.4%, F3 21.3%, and F4 31.8%, p=0.004). Fasting glycemia also increased with the degree of fibrosis (F0-F2 5.75±0.18 F3 5.84±0.17, and F4 6.69±0.2 mmol/L, p=0.001). We saw significant decrease of glycemia after treatment in all patients, but patients without T2DM or IFG from 6.21±0.12 to 6.08±0.15 mmol/L (p=0.002). The decrease was also visible in treatment experienced patients and patients with Child-Pugh A cirrhosis. Conclusion: We confirmed that the prevalence of either T2DM or IFG increases in chronic hepatitis C patients with the degree of fibrosis. The predictive factors for T2DM were, besides F4, fibrosis also higher age and BMI. Significant decrease of fasting glycemia after the DAA treatment was observed in the whole cohort and in subgroups of patients with T2DM, IFG, cirrhotic, and treatment experienced patients.


Assuntos
Antivirais/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Intolerância à Glucose/epidemiologia , Hepatite C Crônica/sangue , Fatores Etários , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Jejum/sangue , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/etiologia , Hepacivirus , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
7.
Artigo em Inglês | MEDLINE | ID: mdl-29789486

RESUMO

Prevalence of Hepatitis B is relatively low in developed European countries. However specific subpopulations may exist within each country with markedly different Hepatitis B burden. Roma minority is very numerous in Slovakia and their lifestyle is completely different to non-Roma population. The aim of this study is to map Hepatitis B prevalence in Roma and compare it to non-Roma population and to explore potential socio-economic and health related risk factors. Cross-sectional epidemiology study was performed in Slovakia that included randomly sampled Roma population and geographically corresponding random sampled non-Roma population. Comprehensive questionnaire about risk factors was administered and blood samples were drawn for Hepatitis B serology and virology tests. Altogether 855 participants were included. Global Hepatitis B surface Antigen (HBsAg) positivity rate was 7.7% (i.e., active Hepatitis B) and anti Hepatitis B core IgG antibody (antiHBcIgG) positivity rate was 34.6%. Roma population had significantly higher prevalence of Hepatitis B, both active chronic infection (12.4%; 95% Confidence Interval (CI) 9.58%⁻15.97% versus 2.8%; 95% CI 1.56%⁻4.91%; p < 0.0001) and antiHBcIgG positivity (52.8%; 95% CI 48.17%⁻57.44% versus 25.9%; 95% CI 12.56%⁻20.02%; p < 0.0001) Main risk factors for HBsAg positivity were Roma ethnicity, male sex and tattoo. CONCLUSION: There is a very high prevalence of Hepatitis B in Roma communities in Slovakia, with potential for grave medical consequences.


Assuntos
Hepatite B/etnologia , Roma/estatística & dados numéricos , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Eslováquia/epidemiologia , Fatores Socioeconômicos
8.
J Appl Toxicol ; 38(11): 1377-1387, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29624715

RESUMO

This review describes the synthesis of a wide range of novel tetrahydroacridine derivatives (tiocyanates, selenocyanates, ureas, selenoureas, thioureas, isothioureas, disulfides, diselenides and several tacrine homo- and hetro-hybrids). These tacrine congeners exhibit significant anticholinesterase and cytotoxic properties and may therefore be of considerable potential for the development of new drugs for the treatment of Alzheimer's disease.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Antineoplásicos/química , Antineoplásicos/toxicidade , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Descoberta de Drogas , Humanos , Relação Estrutura-Atividade , Tacrina
9.
J Appl Toxicol ; 37(10): 1132-1139, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28370171

RESUMO

Acridines possess two characteristics that have led many researchers to consider the agents interesting targets for future development as potential farmacophores: the planar acridine skeleton, which is able to intercalate into DNA, and the intense fluorescence of the agents. This review offers a study of the multifunctional character of acridines and the synthesis of novel acridine derivatives, with particular focus being placed on isothiocyanates and their congeners, e.g. thioureas, isothioureas, quaternary ammonium salts and platinum/gold conjugates. The review provides an overview of the structure, spectral properties, DNA binding and biological activity of acridinylthiourea congeners. These acridinylthiourea derivatives display significant cytotoxic activities against different types of cancer cell lines at micromolar concentrations. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Acridinas/síntese química , Acridinas/farmacologia , Dano ao DNA/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Isotiocianatos/síntese química , Isotiocianatos/farmacologia , Proflavina/síntese química , Proflavina/farmacologia , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/farmacologia
10.
Case Rep Med ; 2017: 2760535, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28154579

RESUMO

Background. Pulmonary arterial dissection with chronic pulmonary arterial hypertension as its major cause is a very rare but life-threatening condition. In most cases the main pulmonary trunk is the affected site usually without involvement of its branches. Segmental or lobar pulmonary artery dissection is extremely rare. Case Presentation. We report a unique case of left lower lobe pulmonary artery dissection in a 70-year-old male, with confirmed chronic pulmonary hypertension. To confirm dissection MDCT pulmonary angiography was used. Multiplanar reformation (MPR) images in sagittal, coronal, oblique sagittal, and curved projections were generated. This case report presents morphologic CT features of rare chronic left lobar pulmonary artery dissection associated with chronic pulmonary hypertension at a place of localised pulmonary artery calcification. CT pulmonary angiography excluded signs of thromboembolism and potential motion or flow artefacts. Conclusion. To the best of our knowledge, no case of lower lobe pulmonary artery dissection with flap calcification has been reported yet. CT imaging of the chest is a key diagnostic tool that is able to detect an intimal flap and a false lumen within the pulmonary arterial tree and is preferred in differential diagnosis of rare complications of sustained pulmonary arterial hypertension.

11.
Nucleosides Nucleotides Nucleic Acids ; 35(10-12): 529-535, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27906637

RESUMO

The Roma represents a transnational ethnic group, with a current European population of 8-10 million. The evolutionary process that had the greatest impact on the gene pool of the Roma population is called the founder effect. Renal hypouricemia (RHUC) is a rare heterogenous inherited disorder characterized by impaired renal urate reabsorption. The affected individuals are predisposed to recurrent episodes of exercise-induced nonmyoglobinuric acute kidney injury and nephrolithiasis. To date, more than 150 patients with a loss-of-function mutation for the SLC22A12 (URAT1) gene have been found, most of whom are Asians. However, RHUC 1 patients have been described in a variety of ethnic groups (e.g., Arab Israelis, Iraqi Jews, Caucasians, and Roma) and in geographically noncontiguous countries. This study confirms our previous findings regarding the high frequency of SLC22A12 variants observed. Frequencies of the c.1245_1253del and c.1400C>T variants were found to be 1.92% and 5.56%, respectively, in a subgroup of the Roma population from five regions in three countries: Slovakia, Czech Republic, and Spain. Our findings suggested that the common dysfunction allelic variants of URAT1 exist in the general Roma population and thus renal hypouricemia should be kept in differential diagnostic algorithm on Roma patients with defect in renal tubular urate transport. This leads to confirm that the genetic drift in the Roma have increased the prevalence of hereditary disorders caused by very rare variants in major population.


Assuntos
Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Erros Inatos do Transporte Tubular Renal/genética , Roma/genética , Cálculos Urinários/genética , Evolução Molecular , Feminino , Efeito Fundador , Frequência do Gene , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Prevalência , Erros Inatos do Transporte Tubular Renal/epidemiologia , Deleção de Sequência , Cálculos Urinários/epidemiologia
12.
J Inorg Biochem ; 161: 52-62, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27230386

RESUMO

Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-ß (A-ß) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-ß1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease.


Assuntos
Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Inibidores da Colinesterase , Cobre/química , Cumarínicos , Estresse Oxidativo , Fragmentos de Peptídeos/química , Tacrina , Doença de Alzheimer/metabolismo , Butirilcolinesterase/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cumarínicos/síntese química , Cumarínicos/química , Proteínas Ligadas por GPI/química , Humanos , Tacrina/síntese química , Tacrina/química
13.
Gastroenterol Res Pract ; 2016: 8682494, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26858755

RESUMO

Aim. To evaluate the compliance and virological response to pegylated interferon alpha 2a treatment of chronic hepatitis B in Roma population compared to majority Caucasian population in Slovakia. Methods. Retrospective evaluation of a cohort of all Roma patients treated with pegylated interferon alpha 2a from 2007 to 2013 in 3 centers for treatment of chronic viral hepatitis B. The Study included 43 Roma patients with chronic viral hepatitis B and randomly selected control group. Treatment duration was 48 weeks. Viral response was evaluated after 24 weeks, at the end of treatment, and 24 weeks after the end of treatment. Results. Complete treatment course was finished by 79.1% of Roma patients compared to all patients from the control group (p = 0.0009). There was a tendency toward lower viral response rate in Roma at all time points; however significant difference was only at end of treatment viral response (51.2% Roma versus 81.4% majority, p = 0.003). We also did not find significant difference at the rate of HBsAg loss. Conclusion. Roma patients with chronic hepatitis B have significantly worse compliance to treatment with pegylated interferon and they have significantly lower rate of end of treatment viral response.

14.
Clin Exp Hepatol ; 2(1): 2-6, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28856264

RESUMO

Opinion leaders in each of four countries in the Central European region summarize the available data on hepatitis C virus (HCV) epidemiology. The overall prevalence of anti-HCV antibody reactivity in this region varies between 0.2% and 2.1%, the most prevalent HCV genotype is GT 1. The commonest route of transmission is intravenous drug abuse at present.

15.
Eur J Gastroenterol Hepatol ; 27(4): 405-11, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25874513

RESUMO

BACKGROUND: Multiple studies have recently proposed the lowering of upper limit of normal (ULN) for alanine aminotransferase (ALT) to improve the diagnostic sensitivity for viral hepatitides and metabolic syndrome (MS). We have tried to validate some of the proposed ULNs in the diagnosis of MS. METHODS: We used data from the HepaMeta Study conducted in 2011 in Slovakia, which explored the prevalence of MS in eastern Slovakia. Patients were tested for the criteria of MS and ALT. Different, previously published, ALT cutoffs were then used to calculate odds' ratios, sensitivity, specificity, and accuracy of MS and its components. RESULTS: Manufacturers' recommended ULN used in our institution (0.8 µkat/l, 47 U/l for men and 0.6 µkat/l, 35 U/l for women) failed to predict any significant risk of MS. Lowered cutoff (72% of the original ULN) identified the patients with the highest age-adjusted probability of MS (odds ratio 3.194, 95% confidence interval 1.398-7.295). ALT was significantly associated with elevated levels of triacylglycerols, hyperglycemia, and obesity. CONCLUSION: In patients with MS, one must consider liver involvement if the patient has ALT levels in the upper third of the reference range. There is the need for discussion about the feasibility of lower ALT ULN in clinical practice.


Assuntos
Alanina Transaminase/sangue , Síndrome Metabólica/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/enzimologia , Pessoa de Meia-Idade , Razão de Chances , Padrões de Referência , Medição de Risco , Sensibilidade e Especificidade
16.
J Med Chem ; 57(16): 7073-84, 2014 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-25089370

RESUMO

A series of novel tacrine derivatives and tacrine-coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Of these compounds, tacrine-coumarin heterodimer 7c and tacrine derivative 6b were found to be the most potent inhibitors of human AChE (hAChE), demonstrating IC50 values of 0.0154 and 0.0263 µM. Ligands 6b, 6c, and 7c exhibited the highest levels of inhibitory activity against human BuChE (hBuChE), demonstrating IC50 values that range from 0.228 to 0.328 µM. Docking studies were performed in order to predict the binding modes of compounds 6b and 7c with hAChE/hBuChE.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cumarínicos/química , Tacrina/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Técnicas de Química Sintética , Inibidores da Colinesterase/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
17.
Bioorg Chem ; 57: 13-29, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25171773

RESUMO

A novel series of trisubstituted acridines were synthesized with the aim of mimicking the effects of BRACO19. These compounds were synthesized by modifying the molecular structure of BRACO19 at positions 3 and 6 with heteroacyclic moieties. All of the derivatives presented in the study exhibited stabilizing effects on the human telomeric DNA quadruplex. UV-vis spectroscopy, circular dichroism, linear dichroism and viscosimetry were used in order to study the nature of the DNA binding in more detail. The results show that all of the novel derivatives were able to fold the single-stranded DNA sequences into antiparallel G-quadruplex structures, with derivative 15 exhibiting the highest stabilizing capability. Cell cycle analysis revealed that a primary trend of the "braco"-like derivatives was to arrest the cells in the S- and G2M-phases of the cell cycle within the first 72h, with derivative 13 and BRACO19 proving particularly effective in suppressing cell proliferation. All studies derivatives were less toxic to human fibroblast cell line in comparison with HT 29 cancer cell line.


Assuntos
Acridinas/química , Acridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , DNA/metabolismo , Quadruplex G/efeitos dos fármacos , Animais , Bovinos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/química , Humanos , Ligantes , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
18.
Int J Biol Macromol ; 70: 435-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25036600

RESUMO

A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ΔΔGtheor, and docking studies elucidate these suggestions in more detail.


Assuntos
Acridinas/química , Inibidores da Colinesterase/química , Piperazinas/química , Tacrina/química , Tioureia/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Ativação Enzimática/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Piperazina , Ligação Proteica
19.
Cent Eur J Public Health ; 22 Suppl: S37-42, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24847613

RESUMO

BACKGROUND: The simultaneous presence of chronic hepatitis B (CHB) and metabolic syndrome (MS) in the high-risk Roma community constitutes a high risk for liver cirrhosis and potentially hepatocellular carcinoma. This study aims to explore the relationship between MS and CHB. METHODS: Data from the cross-sectional HepaMeta Study conducted in Slovakia in 2011 among Roma living in rural communities were used. Participants were tested for the presence of MS, and lipid levels--total cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides (TG), apolipoprotein B100, and CHB HBsAg and anti-HBc IgG were also monitored. Viral load was measured in HBsAg-positive patients. RESULTS: A total of 452 patients were screened; MS was diagnosed in 29.6% of patients, and 12.5% had CHB. Anti-HBc IgG antibodies were present in 52.8% of patients. CHB patients had lower levels of total cholesterol (5.45 +/-1.21 vs. 4.71 +/- 1.23 mmol/l; p = 0.035), LDL cholesterol (median 2.2 mmol/l, interquartile range 0.88 mmol/l vs. 2.5 mmol/l, interquartile range 0.9 mmol/l; p = 0.01) and apolipoprotein B100 (median 0.66 mmol/l, interquartile range 0.26 mmol/l vs. 0.74 mmol/l, interquartile range 0.29 mmol/l; p = 0.025). Patients diagnosed with MS had a higher HBV DNA load than patients without MS (1,728.2 +/- 14.33 IU/ml vs. 12,779.1 +/- 20.9 IU/ml; p = 0.037). CHB patients with TC and apolipoprotein B100 within the reference range had a lower hepatitis B DNA (HBV DNA) load than patients with high or low values of TC or apolipoprotein B100. CONCLUSION: The prevalence of chronic hepatitis B and simultaneous presence of MS was high among Roma. HBsAg-positive patients had lower levels of total and LDL cholesterol along with decreased apolipoprotein B100. The viral load of chronic hepatitis B patients with MS was higher than in patients without MS.


Assuntos
Hepatite B/etnologia , Síndrome Metabólica/etnologia , Roma/estatística & dados numéricos , Adolescente , Adulto , Apolipoproteína B-100/sangue , Biomarcadores/sangue , Colesterol/sangue , Comorbidade , Estudos Transversais , Feminino , Inquéritos Epidemiológicos/métodos , Inquéritos Epidemiológicos/estatística & dados numéricos , Hepatite B/sangue , Humanos , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Roma/etnologia , População Rural/estatística & dados numéricos , Eslováquia/epidemiologia , Triglicerídeos/sangue
20.
Cent Eur J Public Health ; 22 Suppl: S43-50, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24847614

RESUMO

BACKGROUND: Elevated gamma-glutamyl transpeptidase (GGT) is present approximately in half of all patients with non-alcoholic fatty liver disease (NAFLD). NAFLD is the liver manifestation of metabolic syndrome (MS). This study aimed to explore the relationship between GGT and MS or proinflammatory parameters. METHODS: Data from the cross-sectional HepaMeta study conducted in Slovakia in 2011 among Roma living in rural communities were used. Participants (n = 446) were divided into 2 groups; those with elevated GGT and those with normal GGT levels. MS was diagnosed according to the International Diabetes Federation criteria; presence of central obesity and low density lipoproteins (LDL) or high density lipoproteins (HDL), high triglycerides, hypertension, glucose intolerance or type 2 diabetes. Participants were tested for the presence of MS and its components, and biochemical tests for lipid levels (total cholesterol, HDL, LDL, TG) and inflammatory parameters (high sensitivity C-reactive protein--hs-CRP and ferritin) were performed. RESULTS: Of 446 Roma participants, only 29 (6.5%) had GGT levels above the normal value. After exclusion of patients with viral hepatitis and alcohol abuse, patients with elevated GGT suffered from MS more often (p < 0.001), and patients with more MS components had a higher risk of elevated GGT. We found a significant association between GGT and the individual MS components, except HDL (waist circumference > or = 94 cm in men or 80 cm in women: p < 0.01; BMI > 30: p < 0.001; fasting glucose > or = 5.6 mmol/l: p < 0.001; arterial hypertension: p < 0.05, and TAG > or = 1.7 mmol/l: p < 0.001). Patients with elevated GGT levels had also significantly higher hs-CRP (hs-CRP > 2 mg/l: p < 0.001; hs-CRP > 3 mg/l: p < 0.001) and ferritin (ferritin > 300 mg/l: p < 0.01) levels. CONCLUSION: Patients with MS have more significantly elevated levels of GGT. There is a significant association of GGT with individual MS components, except HDL and inflammatory parameters (hs-CRP, ferritin).


Assuntos
Inflamação/sangue , Inflamação/epidemiologia , Síndrome Metabólica/etnologia , Síndrome Metabólica/enzimologia , Roma/estatística & dados numéricos , gama-Glutamiltransferase/sangue , Adolescente , Adulto , Proteína C-Reativa , Comorbidade , Estudos Transversais , Dieta/etnologia , Dieta/métodos , Dieta/estatística & dados numéricos , Fígado Gorduroso/sangue , Fígado Gorduroso/etnologia , Feminino , Ferritinas/sangue , Inquéritos Epidemiológicos/métodos , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Inflamação/etnologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Hepatopatia Gordurosa não Alcoólica , Fatores de Risco , Roma/etnologia , População Rural/estatística & dados numéricos , Eslováquia/epidemiologia , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
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