RESUMEN
Urocortin 2, an endogenous selective ligand for the corticotropin-releasing hormone receptor type 2, has been suggested to exert cardioprotective effects. We analyzed the possible relationship between the level of Ucn2 and specific indicators of cardiovascular risk factors in patients with untreated hypertension and in healthy subjects. Sixty seven subjects were recruited: 38 with newly diagnosed treatment-naive hypertension (with no pharmacological treatment - HT group) and 29 healthy subjects without hypertension (nHT group). We evaluated ambulatory blood pressure monitoring, Ucn2 levels and metabolic indices. Multivariable regression analyses were performed to assess the effects of gender, age, and Ucn2 levels on metabolic indices or blood pressure (BP) level. Log of Ucn2 levels were higher in healthy subjects than in hypertensive patients (2.44±0.7 versus 2.09±0.66, p<.05) and correlated inversely with 24-hour diastolic blood pressure, and both night-time systolic and diastolic blood pressure regardless of age and gender (R2=0.06; R2=0.06; R2=0.052; respectively). Furthermore, Ucn2 levels inversely correlated with cholesterol and low-density cholesterol (LDL) concentrations in healthy subjects only. Ucn2 was independently related to total cholesterol (but not to LDL) regardless of age, gender and the presence of hypertension (R2=0.18). However, we did not find any relationship between urocortin 2, body mass index or waist-hip ratio as well as parameters of glucose metabolism. Our data indicates that higher levels of urocortin 2 are related to more favorable lipid profiles and lower blood pressure.
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Hipertensión , Urocortinas , Humanos , Urocortinas/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Monitoreo Ambulatorio de la Presión Arterial , ColesterolRESUMEN
OBJECTIVE: Negative pressure wound therapy (NPWT) has been used to treat diabetic foot ulcerations (DFUs). Its action on the molecular level, however, is only partially understood. Some earlier data suggested NPWT may be mediated through modification of local gene expression. As methylation is a key epigenetic regulatory mechanism of gene expression, we assessed the effect of NPWT on its profile in patients with type 2 diabetes (T2DM) and neuropathic non-infected DFUs. METHODS: Of 36 included patients, 23 were assigned to NPWT and 13 to standard therapy. Due to ethical concerns, the assignment was non-randomized and based on wound characteristics. Tissue samples were obtained before and 8 ± 1 days after therapy initiation. DNA methylation patterns were checked by Illumina Methylation EPIC kit. RESULTS: In terms of clinical characteristics, the groups presented typical features of T2DM; however, the NPWT group had significantly greater wound area: 16.8 cm2 vs 1.4 cm2 (P = 0.0003). Initially only one region at chromosome 5 was differentially methylated. After treatment, 57 differentially methylated genes were found, mainly located on chromosomes 6 (chr6p21) and 20 (chr20p13); they were associated with DNA repair and autocrine signaling via retinoic acid receptor. We performed differential analyses pre treatment and post treatment. The analysis revealed 426 differentially methylated regions in the NPWT group, but none in the control group. The enrichment analysis showed 11 processes significantly associated with NPWT, of which 4 were linked with complement system activation. All but one were hypermethylated after NPWT. CONCLUSION: The NPWT effect on DFUs may be mediated through epigenetic changes resulting in the inhibition of complement system activation.
RESUMEN
Urocortin 2 (Ucn2) - corticotropin-releasing hormone receptor 2 signalling has favourable effects in the cardiovascular system, including vasodilation, lowering of blood pressure and systemic peripheral resistance, increase in cardiac output and cardiac contractility, as well as cardioprotection against ischemia-reperfusion injury. Vasodilation and lowering of blood pressure seem to be very interesting and important effects, but their mechanism and interaction with the antihypertensive drugs have not been evaluated. The aim of the present study was to assess the relationship between Ucn2 concentration and antihypertensive therapy in patients with primary hypertension. We examined a group of 65 patients with primary hypertension receiving at least 3 antihypertensive drugs. In all of them plasma level of Ucn2, anthropometric measurements, biochemical tests, ambulatory blood pressure monitoring (ABPM), and echocardiography were performed. There were no differences in Ucn2 level related to beta-blockers, calcium channel blockers or diuretics, but we observed that in patients treated with angiotensin converting enzyme inhibitors (ACEI) (n = 52) serum Ucn2 levels were significantly higher than in patients treated with angiotensin-receptor blockers (ARBs) (n = 13) (10.93 versus 5.56 ng/mL; P < 0.05). Moreover, we did not observe any differences in terms of blood pressure on ABPM, biochemical measurements, left ventricular mass index, or presence of diabetes. In addition, in a small subgroup receiving alpha-blockers we also found a lower level of Ucn2, with coexisting higher systolic blood pressure at night, higher left ventricle mass index (LVMI) and more frequent occurrences of diabetes compared to non-alpha-blockers. Our findings suggest that the hypotensive action of renin-angiotensin-aldosterone system blockade may be related to the urocortin system. Ucn2 may be an important element in the mosaic of blood pressure-lowering factors in patients treated for essential hypertension.
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Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Hormona Liberadora de Corticotropina/metabolismo , Hipertensión/tratamiento farmacológico , Urocortinas/metabolismo , Presión Sanguínea/efectos de los fármacos , Monitoreo Ambulatorio de la Presión Arterial/métodos , Bloqueadores de los Canales de Calcio/uso terapéutico , Femenino , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Humanos , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Sistema Renina-Angiotensina/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
AIMS: Negative pressure wound therapy (NPWT) has been successfully used as a treatment for diabetic foot ulceration (DFU). Its mechanism of action on the molecular level, however, is not fully understood. We assessed the effect of NPWT on gene expression in patients with type 2 diabetes (T2DM) and DFU. METHODS: We included two cohorts of patients-individuals treated with either NPWT or standard therapy. The assignment to NWPT was non-randomized and based on wound characteristics. Differential gene expression profiling was performed using Illumina gene expression arrays and R Bioconductor pipelines based on the 'limma' package. RESULTS: The final cohort encompassed 21 patients treated with NPWT and 8 with standard therapy. The groups were similar in terms of age (69.0 versus 67.5 years) and duration of T2DM (14.5 versus 14.4 years). We identified four genes differentially expressed between the two study arms post-treatment, but not pre-treatment: GFRA2 (GDNF family receptor alpha-2), C1QBP (complement C1q binding protein), RAB35 (member of RAS oncogene family) and SYNJ1 (synaptic inositol 1,4,5-trisphosphate 5-phosphatase 1). Interestingly, all four genes seemed to be functionally involved in wound healing by influencing re-epithelialization and angiogenesis. Subsequently, we utilized co-expression analysis in publicly available RNA-seq data to reveal the molecular functions of GFRA2 and C1QBP, which appeared to be through direct protein-protein interactions. CONCLUSIONS: We found initial evidence that the NPWT effect on DFUs may be mediated through differential gene expression. A discovery of the specific molecular mechanisms of NPWT is potentially valuable for its clinical application and development of new therapies.
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Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Pie Diabético/genética , Pie Diabético/terapia , Terapia de Presión Negativa para Heridas , Cicatrización de Heridas/genética , Adulto , Anciano , Proteínas Portadoras/genética , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Pie Diabético/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Proteínas de Unión al GTP rab/genéticaRESUMEN
Blood is considered to be a sterile microenvironment, in which bacteria appear only periodically. Previously used methods allowed only for the detection of either viable bacteria with low sensitivity or selected species of bacteria. The Next-Generation Sequencing method (NGS) enables the identification of all bacteria in the sample with their taxonomic classification. We used NGS for the analysis of blood samples from healthy volunteers (n = 23) and patients with sepsis (n = 62) to check whether any bacterial DNA exists in the blood of healthy people and to identify bacterial taxonomic profile in the blood of septic patients. The presence of bacterial DNA was found both in septic and healthy subjects; however, bacterial diversity was significantly different (P = 0.002) between the studied groups. Among healthy volunteers, a significant predominance of anaerobic bacteria (76.2 %), of which most were bacteria of the order Bifidobacteriales (73.0 %), was observed. In sepsis, the majority of detected taxa belonged to aerobic or microaerophilic microorganisms (75.1 %). The most striking difference was seen in the case of Actinobacteria phyla, the abundance of which was decreased in sepsis (P < 0.001) and Proteobacteria phyla which was decreased in the healthy volunteers (P < 0.001). Our research shows that bacterial DNA can be detected in the blood of healthy people and that its taxonomic composition is different from the one seen in septic patients. Detection of bacterial DNA in the blood of healthy people may suggest that bacteria continuously translocate into the blood, but not always cause sepsis; this observation can be called DNAemia.
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Técnicas Bacteriológicas/métodos , Análisis Químico de la Sangre , ADN Bacteriano/sangre , Voluntarios Sanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Sepsis , Anciano , Bacterias/clasificación , Bacterias/genética , Biodiversidad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Purpose. Products of angiotensin (ANG) I metabolism may predispose to vascular complications of diabetes mellitus. Methods. Diabetes was induced with streptozotocin (75 mg/kg i.p.). Rat aorta fragments, isolated 4 weeks later, were pretreated with perindoprilat (3 µM), thiorphan (3 µM), or vehicle and incubated for 15 minutes with ANG I (1 µM). Products of ANG I metabolism through classical (ANG II, ANG III, and ANG IV) and alternative (ANG (1-9), ANG (1-7), and ANG (1-5)) pathways were measured in the buffer, using liquid chromatography-mass spectrometry. Results. Incubation with ANG I resulted in higher concentration of ANG II (P = 0.02, vehicle pretreatment) and lower of ANG (1-9) (P = 0.048, perindoprilat pretreatment) in diabetes. Preference for the classical pathway is suggested by higher ANG III/ANG (1-7) ratios in vehicle (P = 0.03), perindoprilat (P = 0.02), and thiorphan pretreated (P = 0.02) diabetic rat. Within the classical pathway, ratios of ANG IV/ANG II (P = 0.01) and of ANG IV/ANG III (P = 0.049), but not of ANG III/ANG II are lower in diabetes. Conclusions. Diabetes in rats led to preference toward deleterious (ANG II, ANG III) over protective (ANG IV, ANG (1-9), and ANG (1-7)) ANG I metabolites.
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Angiotensina II/metabolismo , Angiotensina I/metabolismo , Aorta/metabolismo , Diabetes Mellitus Experimental/metabolismo , Angiotensina I/efectos de los fármacos , Angiotensina II/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Aorta/efectos de los fármacos , Cromatografía Liquida , Indoles/farmacología , Espectrometría de Masas , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/farmacología , Ratas , Ratas Sprague-Dawley , Tiorfan/farmacologíaRESUMEN
Coronary artery disease (CAD) remains a major cause of death in developed countries. Both environmental and, less known, genetic factors contribute to progression of CAD to myocardial infarction (MI). Immune system is activated in patients with CAD through dendritic cells (DCs), which present plaque antigens to T lymphocytes. Production of proinflammatory cytokines by activated T cells contributes to plaque rupture in MI. Chemokine receptor 7 (CCR7) on DCs is required for their chemotaxis from plaque to lymph nodes. This makes possible an interaction of DCs with T lymphocytes and initiation of specific immune response. We hypothesized that single nucleotide polymorphisms (SNPs) in CCR7 gene locus are associated with previous MI in patients with CAD. To test this hypothesis, we genotyped six SNPs from the CCR7 gene locus in 300 consecutive patients, admitted for elective coronary angiography. We performed univariate-, multivariate- (including potential confounders) and haplotype-based tests of association of SNPs with previous MI and results of angiography. Allele A of rs17708087 SNP was associated with previous MI. This association remained significant after adjustment for age, sex, smoking, hypercholesterolaemia and drugs used by patients (odds ratio 2.13, 95% confidence interval: 1.13-3.86). Therefore, we conclude that CCR7 gene locus harbours a polymorphism that modifies risk of MI in patients with CAD. Replication of this association could be sought in a prospective cohort of initially healthy individuals.
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Enfermedad de la Arteria Coronaria/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Infarto del Miocardio/genética , Receptores CCR7/genética , Anciano , Alelos , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/patología , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/patología , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
We used mass spectrometry to quantitate production of angiotensinogen metabolites in renal artery of 3- and 7-month-old Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR). Tissue fragments were incubated for 15 min in oxygenated buffer, with added angiotensin I. Concentrations of angiotensins I (ANG I), II (ANG II), III (ANG III), IV (ANG IV), angiotensin (1-9) [ANG (1-9)], angiotensin (1-7) [ANG (1-7)], and angiotensin (1-5) [ANG (1-5)], excreted into the buffer during experiment, were measured using liquid chromatography-mass spectrometry (LC/MS) and expressed per mg of dry tissue. Effects of pretreatment with 10 microM perindoprilat on the production of ANG I metabolites were quantitated. Background production of any of ANG I metabolites differed neither between WKY and SHR rats nor between 3- and 7-month-old rats. Perindoprilat pretreatment of renal arteries resulted, as expected, in decrease of ANG II production. However, renal arteries of 7-month-old SHR rats were resistant to ACE inhibitor and did not change ANG II production in response to perindoprilat. In renal arteries, taken from 3-month-old rats, pretreated with perindoprilat, incubation with ANG I, resulted in the level of ANG (1-9) significantly higher in SHR than WKY rats. Our conclusion is that in SHR rats, sensitivity of renal artery ACE to perindoprilat inhibition changes with age.
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Angiotensina I/metabolismo , Hipertensión/metabolismo , Indoles/farmacología , Fragmentos de Péptidos/metabolismo , Arteria Renal/metabolismo , Envejecimiento/metabolismo , Animales , Técnicas In Vitro , Masculino , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Arteria Renal/efectos de los fármacosRESUMEN
AIM: The development and progression of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) have been associated with poor glycaemic control, long disease duration and other clinical features. However, the pathogenesis of the complication is still poorly understood. As the formation of dense fibrin clots resistant to lysis has been described in diabetes patients, this study tested the hypothesis that altered clot structure and function are associated with DR in T2DM patients. METHODS: The study included 101 T2DM subjects without DR (NDR) and 60 with DR. Plasma fibrin-clot permeation was assessed using a pressure-driven system, and expressed as the permeation coefficient (K(s)), indicating pore size, and as the time required for a 50% decrease in clot turbidity (t(50%)) as a marker of susceptibility to fibrinolysis. All patients underwent ophthalmological examination. Clinical and biochemical co-variables were also measured. Determinants of DR were identified using stepwise, multivariable, logistic-regression analyses. RESULTS: Patients with DR had lower clot permeability (K(s): 6.15 ± 1.18 vs. 7.53 ± 1.24 10(-9) cm(2); P < 0.0001) and slower fibrin-clot lysis (t(50%): 10.12 ± 1.24 vs. 9.12 ± 1.4 min; P < 0.0001) than NDR subjects. Logistic analysis revealed associations between DR and K(s), t(50%), fasting glucose and diabetes duration, as well as insulin treatment and statin non-use (P < 0.05). After adjusting for these variables as well as for age and gender, associations between K(s) and t(50%) with DR proved to be significant. CONCLUSION: Formation of compact fibrin clots and impaired clot lysis are both associated with DR in T2DM patients. However, it is unclear whether these abnormalities lead to the development of DR or merely constitute a marker of its presence.
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Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/metabolismo , Retinopatía Diabética/metabolismo , Fibrina/metabolismo , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/fisiopatología , Retinopatía Diabética/fisiopatología , Femenino , Fibrina/química , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) are the treatment of choice for patients with Alzheimer's disease (AD). However, their efficacy is moderate and differs from patient to patient. Recent studies suggest that the Q192R variant of the paraoxonase 1 gene (PON1) might affect individual susceptibility to these drugs. METHODS: We investigated the influence of 3 single nucleotide polymorphisms (SNPs) in PON1 (rs 662, rs 854560, rs 705381) and the APOE common polymorphism in 101 Polish patients with late-onset AD in response to treatment with AChEIs. RESULTS: No significant differences were observed between carriers and non-carriers of the PON1 SNPs or the APOE common polymorphism in terms of treatment response. These results did not change after stratification of APOE status. CONCLUSION: Our results suggest that both the investigated PON1 and APOE common SNPs do not influence treatment response to AChEIs in patients with AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Arildialquilfosfatasa/genética , Anciano , Apolipoproteínas E/genética , Inhibidores de la Colinesterasa/uso terapéutico , ADN/genética , Donepezilo , Femenino , Haplotipos , Heterocigoto , Humanos , Indanos/uso terapéutico , Masculino , Pruebas Neuropsicológicas , Fenilcarbamatos/uso terapéutico , Piperidinas/uso terapéutico , Polimorfismo Genético/genética , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , RivastigminaRESUMEN
BACKGROUND: The relationship between different paraoxonase (PON) gene polymorphisms and the risk of Alzheimer's disease (AD) was studied several times and the results were controversial. METHODS: We investigated the association of 4 single-nucleotide polymorphisms (SNPs) of the PON1 (M55L; Q192R; -161C/T) and the PON2 (C311S) genes that were shown to affect the risk of sporadic AD. We studied 360 Caucasian cases with late-onset AD and 354 nondemented controls. RESULTS: No significant differences were observed between the studied PON SNPs and AD risk. The results did not change after stratification of the apolipoprotein E status. Meta-analyses of studies in Caucasians assessing the associations between the PON1 M55L, -161C/T and Q192R SNPs and the risk of AD were performed, and no associations were found. CONCLUSION: Our results suggest that the studied PON1 and PON2 polymorphisms are not associated with late-onset AD.
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Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Arildialquilfosfatasa/genética , Polimorfismo Genético/genética , Factores de Edad , Edad de Inicio , Anciano , Alelos , Apolipoproteínas E/genética , ADN/genética , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Polonia/epidemiología , Polimorfismo de Nucleótido Simple , Población , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Regresión , Factores de Riesgo , Factores SexualesAsunto(s)
Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/genética , Polimorfismo Genético , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Distribución de Chi-Cuadrado , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. It was also proved that Ang II promotes atherogenesis. Angiotensin-(1-7) [Ang-(1-7)] opposites Ang II action. Therefore, we would like to find out whether Ang-(1-7) receptor agonist: AVE 0991, could ameliorate atherosclerosis progression in an experimental model of atherosclerosis: apolipoprotein E (apoE) - knockout mice. AVE 0991 inhibited atherogenesis, measured both by "en face" method (7.63+/-1.6% vs. 14.6+/-2.1%) and "cross-section" method (47 235+/-7 546 microm(2) vs. 91 416+/-8 357 microm(2)). This is the first report showing the effect of AVE 0991 on atherogenesis in gene-targeted mice.
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Apolipoproteínas E/genética , Aterosclerosis/prevención & control , Imidazoles/farmacología , Proteínas Proto-Oncogénicas/agonistas , Receptores Acoplados a Proteínas G/agonistas , Animales , Aterosclerosis/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proto-Oncogenes MasRESUMEN
Interleukin-1 is a potent proinflammatory cytokine involved in the pathophysiology of Alzheimer's disease (AD). We genotyped IL-1beta (-511 C/T) and the apolipoprotein E (APOE) common polymorphisms in a large case-controlled study in a Polish population. We included 332 patients with late-onset AD and 220 controls without any neurological deficit, cognitive complaints and history of neurological diseases, aged > or = 65 years. The distribution of the IL-1beta (-511 C/T) genotypes was similar to that in the controls (AD: C/C = 45.8%, C/T = 44.6%, T/T = 9.6% vs. controls: C/C = 53.9%, C/T = 38.3%, T/T = 7.3%, p > 0.05). Our study confirms previous reports that APOE epsilon4 is strongly related to the risk of AD (odds ratio = 6.60, 95% confidence interval 4.19-10.41). APOE status did not affect the distribution of the studied IL-1beta polymorphism. The IL-1beta (-511 C/T) polymorphism is not a risk factor for late-onset AD in a Polish population.
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Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Interleucina-1beta/genética , Polimorfismo Genético , Edad de Inicio , Anciano , Anciano de 80 o más Años , Apolipoproteína E4/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Humanos , Masculino , Polonia/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is the major inhibitor of fibrinolysis. It was reported that PAI-1 gene polymorphisms affected PAI-1 level and might therefore influence the risk of vascular diseases, including stroke. We studied the association of three common polymorphisms in PAI-1 gene (-844 G/A, -675 4G/5G, and HindIII G/C) with the odds of different causes of ischemic stroke. METHODS: We studied 390 patients with ischemic stroke due to large vessel disease (n = 117), small vessel disease (n = 121), and cardioembolism (n = 152) as well as 291 controls. The etiology of ischemic stroke was established using TOAST criteria. PAI-1 polymorphisms were genotyped with restriction fragment length polymorphism and single strand conformation polymorphism method. RESULTS: A-G-4G haplotype of PAI-1 gene was found more frequently in stroke patients with small vessel disease than in control subjects (44.9% vs 35.7%; P = 0.02). No association was found between investigated genotype or allele frequencies and distinct causes of ischemic stroke. CONCLUSIONS: Our results demonstrate that A-G-4G PAI-1 gene haplotype is associated with increased risk of small vessel disease stroke, but this study does not support an association of -844 G/A, -675 4G/5G, and HindIII G/C PAI-1 gene polymorphisms with particular etiology of ischemic stroke.
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Isquemia Encefálica/etiología , Enfermedades Arteriales Cerebrales/complicaciones , Enfermedades Arteriales Cerebrales/genética , Embolia Intracraneal/complicaciones , Inhibidor 1 de Activador Plasminogénico/genética , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/genética , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Embolia Intracraneal/genética , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de Riesgo , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/genéticaRESUMEN
Nebivolol is a novel beta1-blocker with a nitric oxide (NO)--potentiating, vasodilatory effect that is unique among beta-blockers. It was already shown that nebivolol ameliorates atherosclerosis in cholesterol-fed rabbits. We, therefore, wanted to investigate whether this is the case in the fine experimental model of atherosclerosis: apolipoprotein E (apoE)-knockout mice. Nebivolol attenuated atherogenesis, measured both by "en face" method (9.23+/-1.8% vs. 14.6+/-2.1%) and "cross-section" method (63125+/-8455 microm(2) vs. 91416+/-8357 m(2)). This is the first report showing the effect of nebivolol on atherogenesis in gene-targeted mice.
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Antagonistas de Receptores Adrenérgicos beta 1 , Antagonistas Adrenérgicos beta/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Benzopiranos/uso terapéutico , Etanolaminas/uso terapéutico , Vasodilatadores/uso terapéutico , Animales , Aorta/efectos de los fármacos , Aorta/patología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/sangre , Aterosclerosis/patología , Colesterol/sangre , Femenino , Ratones , Ratones Noqueados , Nebivolol , Índice de Severidad de la Enfermedad , Triglicéridos/sangreRESUMEN
We have shown that inhibitors of five lipoxygenase activating protein (FLAP)--MK-886 and BAYx1005 inhibit atherosclerosis in apolipoprotein E/LDL receptor-double knockout mice. We, therefore, investigated whether cysteinyl leukotrienes receptor inhibitor--montelukast, given at a dose of 0.125 microg per 100 mg of body weight per day during 16 weeks, could also attenuate atherogenesis. In apoE/LDLR-DKO mouse model montelukast significantly decreased atherogenesis, measured both by "en face" method (25.5+/-2.% vs. 17.23 +/- 1.8%) and "cross-section" method (455,494 +/- 26,477 microm(2) vs. 299,201 +/- 20,373 microm(2)). The results were, however, less pronounced, comparing to FLAP inhibitors. This is the first report showing the effect of montelukast on atherogenesis in gene-targeted mice.
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Acetatos/uso terapéutico , Apolipoproteínas E/genética , Aterosclerosis/prevención & control , Antagonistas de Leucotrieno/uso terapéutico , Quinolinas/uso terapéutico , Receptores de LDL/genética , Animales , Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/patología , Colesterol/sangre , Ciclopropanos , Femenino , Lípidos/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/patología , Sulfuros , Triglicéridos/sangreRESUMEN
Inhibition of angiotensin converting enzyme (ACE) has proved to be beneficial in the treatment of various cardiovascular disorders. The aim of this study was to evaluate ACE inhibitory potential of two polyphenolic compounds with different structures: resveratrol (present in high quantities in French wine) and kaempferol (abundant in greens), using method of liquid chromatography coupled with electrospray ionization mass spectrometry (LC-ESI-MS) for ex vivo measurement of angiotensin I to angiotensin II conversion by ACE in aortic tissue of Wistar-Kyoto rats. In this setting, kaempferol (10-30-100 microM), but not resveratrol (10-30-100 microM) appeared to inhibit dose-dependently conversion of Ang I to Ang II. Although the mechanism of ACE inhibition by kaempferol remains to be elucidated, this observation may help in search or designing of new classes of ACE inhibitors.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Quempferoles/farmacología , Peptidil-Dipeptidasa A/metabolismo , Estilbenos/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Quempferoles/química , Masculino , Ratas , Ratas Endogámicas WKY , Resveratrol , Estilbenos/químicaRESUMEN
The metabolism of renin-angiotensin system (RAS) is more complicated than previously expected and understanding the biological phenomena regulated by variety of angiotensin metabolites requires their precise and possibly comprehensive quantitation. Physiological concentrations of angiotensins (Ang) in biological fluids are low, therefore their accurate measurements require very sensitive and specific analytical methods. In this study we developed an accurate and reproducible method of quantitation of angiotensin metabolites through coupling of liquid chromatography and electrospray ionization - mass spectrometry (LC-ESI-MS). With this method main angiotensin metabolites (Ang I, II, III, IV, 1-9, 1-7, 1-5) can be reliably measured in organ bath of rat tissues (aorta, renal artery, periaortal adipose tissue) and in medium of cultured endothelial cells (EA.hy926), exposed to Ang I for 15 minutes, in the absence or in the presence of angiotensin converting enzyme inhibitor, perindoprilat. Presented LC-ESI-MS method proved to be a quick and reliable solution to comprehensive analysis of angiotensin metabolism in biological samples.
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Angiotensinas/análisis , Angiotensinas/metabolismo , Cromatografía Liquida/métodos , Espectrometría de Masa por Ionización de Electrospray/métodos , Secuencia de Aminoácidos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Angiotensinas/normas , Animales , Línea Celular , Línea Celular Tumoral , Medios de Cultivo Condicionados/análisis , Medios de Cultivo Condicionados/metabolismo , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Hibridomas , Indoles/farmacología , Masculino , Modelos Biológicos , Técnicas de Cultivo de Órganos/métodos , Ratas , Ratas Endogámicas WKY , Estándares de Referencia , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
BACKGROUND: The human paraoxonase (PON) gene family consists of three members, PON1, PON2, and PON3, located adjacent to each other on chromosome 7. PON catalytic activity may be influenced by frequent amino acid variants. Chronic exposure to certain chemicals or to environmental factors causing enhanced lipid peroxidation metabolized by paraoxonases may be a risk factor for sporadic ALS (sALS). OBJECTIVE: The aim of this study was to examine the association between PON1 Q192R, PON1 L55M, and PON2 C311S functional polymorphisms and the risk of sALS in a Polish population. METHODS: The authors included 185 patients with a definite or probable diagnosis of sALS (El Escorial Criteria) and 437 healthy controls of similar age and gender. The paraoxonase polymorphisms were studied by PCR and restriction enzyme digestion. RESULTS: Using logistic regression analyses, the C allele of the C311S polymorphism was associated with sALS in dominant and additive models, whereas the R allele of the Q192R polymorphism was associated with sALS in recessive, additive, and dominant models. The authors compared the distribution of haplotypes between cases and controls. The R-C haplotype was overrepresented among cases (odds ratio 3.44, 95% CI: 1.55 to 7.62, p = 0.002). CONCLUSIONS: Frequent amino acid variants in the paraoxonase 1 and paraoxonase 2 genes are associated with sporadic ALS in a Polish population.