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1.
J Mol Recognit ; 30(5)2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27921323

RESUMO

The HERV-W family of human endogenous retroviruses represents a group of numerous sequences that show close similarity in genetic composition. It has been documented that some members of HERV-W-derived expression products are supposed to play significant role in humans' pathology, such as multiple sclerosis or schizophrenia. Other members of the family are necessary to orchestrate physiological processes (eg, ERVWE1 coding syncytin-1 that is engaged in syncytiotrophoblast formation). Therefore, an assay that would allow the recognition of particular form of HERV-W members is highly desirable. A peptide nucleic acid (PNA)-mediated technique for the discrimination between multiple sclerosis-associated retrovirus and ERVWE1 sequence has been developed. The assay uses a PNA probe that, being fully complementary to the ERVWE1 but not to multiple sclerosis-associated retrovirus (MSRV) template, shows high selective potential. Single-stranded DNA binding protein facilitates the PNA-mediated, sequence-specific formation of strand invasion complex and, consequently, local DNA unwinding. The target DNA may be then excluded from further analysis in any downstream process such as single-stranded DNA-specific exonuclease action. Finally, the reaction conditions have been optimized, and several PNA probes that are targeted toward distinct loci along whole HERV-W env sequences have been evaluated. We believe that PNA/single-stranded DNA binding protein-based application has the potential to selectively discriminate particular HERV-W molecules as they are at least suspected to play pathogenic role in a broad range of medical conditions, from psycho-neurologic disorders (multiple sclerosis and schizophrenia) and cancers (breast cancer) to that of an auto-immunologic background (psoriasis and lupus erythematosus).


Assuntos
DNA de Cadeia Simples/metabolismo , Proteínas de Ligação a DNA/metabolismo , Retrovirus Endógenos/genética , Ácidos Nucleicos Peptídicos/metabolismo , DNA de Cadeia Simples/química , Proteínas de Ligação a DNA/química , Humanos , Modelos Moleculares , Esclerose Múltipla/virologia , Ácidos Nucleicos Peptídicos/química , RNA Viral/metabolismo
2.
Pharmacol Rep ; 68(2): 329-37, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26922535

RESUMO

BACKGROUND: Incretin-based therapies in the treatment of type 2 diabetes mellitus are associated with significant improvements in glycemic control, which are accompanied by a beneficial impact on atherosclerosis. Macrophages are essential in the development of atherosclerotic plaques and may develop features that accelerate atherosclerosis (classically activated macrophages) or protect arterial walls against it (alternatively activated macrophages). Therefore, we explored whether beneficial actions of exenatide are connected with the influence on the macrophages' phenotype and synthesis of inflammatory and anti-inflammatory cytokines. METHODS: Monocytes/macrophages were harvested from 10 healthy subjects. Cells were cultured in the presence of exenatide, exendin 9-39 (GLP-1 antagonist), LPS, IL-4, PKI (PKA inhibitor) and triciribine (PKB/Akt inhibitor). We measured the effects of the above-mentioned compounds on markers of macrophages' phenotype (inducible nitrous oxide (iNOS), arginase 1 (arg1) and mannose receptors) and concentration of nitrite, IL-1ß, TNF-α and IL-10. RESULTS: Exenatide significantly increased the level of IL-10 and decreased both TNF-α and IL-1ß in LPS-treated monocytes/macrophages. Furthermore exenatide increased the expression of arg1-a marker of classical activation and reduced the LPS-induced expression of iNOS-a marker of classical activation. According to experiments with protein kinases inhibitors we found that proinflammatory markers were protein kinase A dependent, whereas the activation of alternative activation was similarly reliant on protein kinase A and B/Akt. CONCLUSIONS: We showed that exenatide skewed the macrophages phenotype toward anti-inflammatory phenotype and this effect is predominantly attributable to protein kinase A and to a less extent to B/Akt activation.


Assuntos
Anti-Inflamatórios/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Peçonhas/farmacologia , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Exenatida , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Monócitos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
Microvasc Res ; 103: 26-35, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26477504

RESUMO

Sulodexide (SDX) is widely used in the treatment of both arterial and venous thrombotic disorders. In addition to its recognized antithrombotic action, SDX has endothelial protective potential, which is independent of the coagulation/fibrinolysis system. However, the detailed molecular mechanisms of the endothelioprotective action of the drug are still unresolved. The aim of the present study was to determine whether treatment with SDX at concentrations of 0.125-0.5 lipase releasing unit (LRU)/ml have on the expression and activity of antioxidant enzymes in ischemic endothelial cells and how these effects might be related to the antiapoptotic properties of SDX. In the present study, human umbilical vein endothelial cells (HUVECs) were subjected to ischemia-simulating conditions (combined oxygen and glucose deprivation, OGD) for 6h to determine the protective effects of SDX. SDX (0.25 and 0.5LRU/ml) in OGD significantly increased the cell viability and prevented mitochondrial depolarization in the HUVECs. Moreover, SDX protected the HUVECs against OGD-induced apoptosis. At concentrations of 0.25 and 0.5LRU/ml, the drug increased both superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPx1) mRNA/protein expression together with a significant attenuation of oxidative stress in ischemic HUVECs. Our findings also demonstrate that an increase in both SOD and GPx activity is involved in the protective effect of SDX on ischemic endothelial cells. Altogether, these results suggest that SDX has a positive effect on ischemia-induced endothelial damage because of its antioxidant and antiapoptotic properties.


Assuntos
Antioxidantes/farmacologia , Glucose/deficiência , Glutationa Peroxidase/metabolismo , Glicosaminoglicanos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Apoptose/efeitos dos fármacos , Hipóxia Celular , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Glutationa Peroxidase/genética , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Fatores de Tempo , Regulação para Cima , Glutationa Peroxidase GPX1
5.
Pharmacol Rep ; 58(5): 729-35, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17085865

RESUMO

The aim of this study was to evaluate the levels of lipid and extralipid parameters in patients with atherogenic dyslipidemia. We investigated the lipid-lowering therapeutic efficacy of fenofibrate and its extralipid influence on oxidized low-density lipoprotein (oxLDL), C-reactive protein (CRP), Fibrinogen, factor VII and plasminogen activator type 1 (PAI-1) during 1-month treatment. Fourteen individuals with HLPIIb were treated with micronized fenofibrate (267 mg/d) for 1 month. The control group included twelve volunteers. Lipidograms were determined with enzymatic kits. ELISA method was used to measure oxLDL and PAI-1. Plasma CRP levels were measured spectrophotometrically. Fibrinogen and factor VII serum levels were evaluated with automatic coagulometer. After 1-month therapy with micronized fenofibrate, we observed a significant reduction of total cholesterol (TC) (277.2 to 217.8 mg/dl, p < 0.05), LDL (183.6 to 129.4 mg/dl, p < 0.05), trigliceryde (TG) (316.7 to 220.6 mg/dl, p < 0.05), oxLDL (68.7 +/- 5.5 to 39.7 +/- 3.7 U/l, p < 0.001) and increase in high-density lipoprotein (HDL) (35.1 to 41.9 mg/dl, p < 0.05). Fibrate treatment also decreased CRP(5.81 +/- 0.26 to 5.08 +/- 0.06 mg/l, p < 0.001), PAI-1 (120.4 +/- 9.7 to 84.7 +/- 5.9 ng/ml; p < 0.05), fibrinogen (3.65 +/- 0.17 to 3.44 +/- 0.16 g/l, ns) and factor VII (159.7% +/- 56.7 to 141% +/- 42.4, ns). The micronized fenofibrate at a daily dose of 267 mg demonstrated a highly beneficial effect on all lipid parameters and advantageous influence on inflammatory and thrombogenic plasma risk factors in patients with dyslipidemia HLPIIb.


Assuntos
Proteína C-Reativa/metabolismo , Fator VII/metabolismo , Fenofibrato/farmacologia , Fibrinogênio/metabolismo , Hiperlipoproteinemia Tipo II/sangue , Hipolipemiantes/farmacologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Adulto , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/sangue , Feminino , Fenofibrato/química , Humanos , Hipolipemiantes/química , Lipoproteínas LDL/sangue , Masculino , Microquímica , Pessoa de Meia-Idade
6.
J Cardiovasc Pharmacol ; 46(3): 377-86, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16116345

RESUMO

Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)alpha activators (fibrates) proved to be effective in the primary and secondary prevention of cardiovascular diseases. The benefits of hypolipemic therapy in cardiovascular diseases cannot be explained only by the lipid-lowering potential of these agents. The aim of this study was to clarify the effect of hypolipemic agents on proinflammatory cytokine release from human monocytes in relationship with their action on plasma levels of sensitive systemic marker of low-grade vascular inflammation. Plasma lipid and high-sensitivity C-reactive protein (hsCRP) levels, and the release of tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta from monocytes were assessed at baseline and 30 and 90 days following randomization of IIa dyslipidemic patients into fluvastatin or simvastatin groups and randomization of type IIb dyslipidemic patients to the micronized form of either ciprofibrate or fenofibrate. Lipopolysaccharide-stimulated monocytes from dyslipidemic patients released significantly more TNFalpha (types IIa and IIb dyslipidemias) and interleukin-1beta (type IIa dyslipidemia) in comparison with monocytes in 59 age-, sex-, and weight-matched control subjects. Their baseline hsCRP levels were also higher. Both statins and fibrates reduced the release of TNFalpha and interleukin-1beta, and lowered plasma hsCRP levels. The effects of hypolipemic agents on cytokine release and plasma hsCRP were unrelated to their lipid-lowering action. Our results have demonstrated that type IIa and IIb dyslipidemic patients exhibit the abnormal pattern of TNFalpha and interleukin-1beta production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARalpha activators normalize monocytic secretion of these cytokines, and this action may partially contribute to the systemic antiinflammatory effect of hypolipemic agents. The statin- and fibrate-induced suppression of proinflammatory cytokine release from monocytes seems to play a role in their beneficial effect on the incidence of cardiovascular events.


Assuntos
Ácido Clofíbrico/farmacologia , Dislipidemias/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipolipemiantes/farmacologia , Interleucina-1/metabolismo , Monócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Anticolesterolemiantes/farmacologia , Proteína C-Reativa/metabolismo , Ácido Clofíbrico/análogos & derivados , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Dislipidemias/sangue , Dislipidemias/etiologia , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Ácidos Fíbricos , Fluvastatina , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Indóis/farmacologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , PPAR alfa/efeitos dos fármacos
7.
Pol J Pharmacol ; 56(6): 837-42, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15662098

RESUMO

The aim of the study was to evaluate the in vivo and in vitro effects of antidepressant drugs on cytotoxic activity of rat spleen macrophages. In the in vivo experiment, rats were injected subcutaneously with two different doses (2 or 10 mg/kg) of desipramine, fluvoxamine and fluoxetine. The drugs were given once, for 2, 4 or 8 weeks. In the in vitro experiment, spleen macrophages were cultured with three different concentrations of desipramine (3.75, 0.75, or 0.075 mM), fluvoxamine (3.14, 0.62, or 0.062 mM), and fluoxetine (3.23, 0.64, or 0.064 mM) for 72 h. The cytotoxic activity of macrophages was evaluated by measuring the lysis of ((51)Cr) chromate-labelled P-815 target cells. In the in vivo experiment, a single dose of fluvoxamine (2 and 10 mg/kg) and fluoxetine (10 mg/kg) significantly decreased macrophage cytotoxic activity. Fluvoxamine (2 and 10 mg/kg), fluoxetine (10 mg/kg) and desipramine (10 mg/kg) administrated for 14 days also decreased macrophage cytotoxic activity. Twenty-eight day treatment with desipramine (2 and 10 mg/kg) decreased macrophage cytotoxic activity. Desipramine, fluvoxamine and fluoxetine given for 56 days did not affect macrophage cytotoxic activity. In the in vitro experiment, antidepressant drugs did not affect the cytotoxic activity of macrophages. The results of the study indicate that the effects of antidepressant drugs on macrophage cytotoxic activity depend on the drug type, dose and duration of the treatment.


Assuntos
Antidepressivos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Animais , Desipramina/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Fluoxetina/farmacologia , Fluvoxamina/farmacologia , Masculino , Ratos , Ratos Wistar , Baço/citologia
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