RESUMEN
BACKGROUND: Accumulating evidence suggests that elevated plasma homocysteine (Hcy), prevalent in hypertensive patients, affects oxidant/antioxidant balance of the body, and is linked to the development of atherosclerosis, inflammation, and endothelium injury. Our objective was to examine a hypothesis that Hcy is a predictor of total antioxidant status (TAS) and endothelial progenitor cells (EPCs), important in the repair of injured endothelium, in hypertensive patients. METHODS: This study was conducted with newly diagnosed essential hypertension patients (n=42) and healthy controls (n=20). Anthropometric and biochemical characteristics, including plasma Hcy, lipids, TAS, and C-reactive protein (CRP) were quantified. Intima-media thickness (IMT) was assessed in carotid arteries. Blood derived EPCs were quantified using an in vitro culture assay. RESULTS: Hcy, IMT, and CRP were significantly elevated while TAS and EPCs were significantly lower in hypertensive patients compared with controls. In multivariate regression analysis Hcy was a predictor of IMT of carotid artery and EPCs number. CONCLUSIONS: Our results suggest that Hcy might increase carotid artery IMT by reducing EPCs numbers. Possible involvement of Hcy in the reduction of EPCs number in hypertensive patients might be in part mediated by Hcy influence on the TAS.
Asunto(s)
Grosor Intima-Media Carotídeo , Homocisteína/sangre , Hipertensión/patología , Hipertensión/fisiopatología , Células Madre/patología , Adulto , Antioxidantes/metabolismo , Endotelio/patología , Humanos , Hipertensión/sangre , Hipertensión/diagnóstico , Estrés OxidativoRESUMEN
BACKGROUND: The accumulation of mutagenic substances in the human body may result in DNA metabolism disruption followed by carcinogenesis. As a consequence of mutations in the genes coding for transmembrane protein pumps, the intracellular concentration of xenobiotics may significantly increase. This, in turn, may provoke altered risk for cancer development. The gene known to be the most relevant in the transport of numerous compounds is ABCB1 (also known as MDR1). Numerous mutations and polymorphisms that affect the encoded protein's (PgP) function were identified in this gene. The aim of the study was to define the frequency of 2677G>A,T and 3435C>T polymorphisms in a population of Polish breast cancer patients and to estimate their contribution to cancer development. METHODS: The polymorphism frequency analysis (209 patients vs. 202 control subjects) was performed either by allele-specific amplification (2677G>A,T) or by restriction fragment length polymorphism (RFLP) using the SAU3AI restriction enzyme (3435C>T) followed by verification with hybridization probe assays in a Real-Time system and sequencing. RESULTS: In the control group the frequency of individual 2677 genotypes was: wild homozygous GG = 34%, heterozygous G/T or G/A = 52.5% and variant homozygous AA or TT = 13.5%, while the genotype frequency in the group of studied patients was 43.5, 44.5 and 12%, respectively. In the control group, the frequency of individual 3435 genotypes was: CC = 25.4%, CT = 50.2%, TT = 24.4%, while the genotype frequency in the group of studied patients was 23, 46 and 31%, respectively. CONCLUSION: Thus, no significant differences in the studied polymorphism frequencies were observed. It is then suggested that the studied polymorphisms, although probably good candidates in other tissue cancer types, might not be good predictive factors in breast cancer risk or development in Caucasians.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Neoplasias de la Mama/genética , Polimorfismo Genético , Subfamilia B de Transportador de Casetes de Unión a ATP , Anciano , Análisis del Polimorfismo de Longitud de Fragmentos Amplificados , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Polonia/epidemiología , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Riesgo , Análisis de Secuencia de ADN/métodosRESUMEN
The influence of an antiestrogen, indole-3-carbinol (I3C) on the expression of CYP1A1, CYP1B1 and AhR genes was investigated in an attempt to establish whether I3C could increase the expression of genes involved in estrone metabolism. Another purpose was to examine the proliferation of an estrogen-dependent breast cancer cell (MCF-7 line) under the influence of I3C and both I3C and DDT. In MCF-7 cells incubated with I3C or I3C and DDT combined, quantitative RT-PCR analysis revealed a significant increase in the level of CYP1A1, AhR, and CYP1B1 transcripts. The proliferation rate of MCF-7 cells was increased by treatment with DDT or estradiol (E2), whereas I3C did not affect the proliferation of MCF-7 cells but greatly reduced the stimulatory effect of DDT, and abolished the effect of E2. The level of p21 transcript, encoding p21 protein involved in the cell cycle, was increased several-fold by I3C comparing to its level in cells incubated with estradiol or DDT. The results suggest that the proliferation of MCF-7 cells is accompanied not only by expression of genes encoding cytochromes involved in estrogen metabolism, but also by changes in the expression of other genes including that encoding p21 protein involved in the cell cycle.
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Hidrocarburo de Aril Hidroxilasas/genética , Citocromo P-450 CYP1A1/genética , Indoles/farmacología , Receptores de Hidrocarburo de Aril/genética , Antineoplásicos/farmacología , Neoplasias de la Mama , División Celular/efectos de los fármacos , Línea Celular Tumoral , Citocromo P-450 CYP1B1 , Estradiol/farmacología , Moduladores de los Receptores de Estrógeno/farmacología , Estrona/metabolismo , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , HumanosRESUMEN
We analyzed protein kinase R (PKR)-binding domain sequences of hepatitis C virus (HCV) NS5A protein and the profile of HCV-specific antibodies from pretreatment sera of HCV-chronically infected patients. Results were compared with clinical data to verify their influence on the course and result of therapy. Of 9 patients enrolled in a 12-month treatment with pegylated interferon alpha (PEG-IFN-alpha) plus ribavirin (RBV), 6 patients responded to therapy, as assessed by the lack of HCV RNA in their sera, and 3 did not. Among 8 HCV-1b-infected patients, those who responded did not have significantly more mutations in the IFN sensitivity determining region (ISDR) compared to non-responders (P = 0.637). Similarly, in the remaining 26-amino acid region of the PKR-binding domain, behind ISDR, the number of mutations did not differ significantly between the two groups (P = 0.796). A correlation was found between the presence of envelope 2 (E2)-specific antibodies and the result of treatment (P = 0.048). This pilot study indicates that mutations in the PKR-binding domain of HCV genotype 1b do not correlate with outcome of PEG-IFN-alpha/RBV therapy. However, the presence of E2-specific antibodies in the pretreatment sera of HCV-chronically infected individuals could serve as a prognostic marker predicting the result of treatment, before its initiation.
Asunto(s)
Hepacivirus/inmunología , Anticuerpos contra la Hepatitis C/sangre , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Proteínas Quinasas/metabolismo , Proteínas no Estructurales Virales/genética , Adulto , Secuencia de Aminoácidos , Antivirales/uso terapéutico , Biomarcadores/sangre , Farmacorresistencia Viral , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Humanos , Técnicas para Inmunoenzimas , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Proyectos Piloto , Polietilenglicoles , Pronóstico , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/uso terapéutico , Resultado del Tratamiento , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Homocysteine (Hcy)-thiolactone mediates protein N-homocysteinylation in humans. Protein N-linked Hcy comprises a major pool of Hcy in human blood, greater that the "total" Hcy pool. N-homocysteinylated proteins are structurally different, compared with native proteins, and are thus likely to be recognized as neoself antigens and induce an autoimmune response. This study was undertaken to provide evidence for anti-Nepsilon-Hcy-Lys-protein antibody and to examine associations between the antibody level, Hcy, and stroke in humans. METHODS: ELISA was used to quantify anti-Nepsilon-Hcy-Lys-protein antibodies in human serum. RESULTS: We found that autoantibodies that specifically recognize Nepsilon-Hcy-Lys epitope on Hcy-containing proteins occur in humans. Serum levels of anti-Nepsilon-Hcy-Lys-protein autoantibodies positively correlate with plasma total Hcy levels, but not with plasma cysteine or methionine levels. In a group of exclusively male patients with stroke, mean level of anti-Nepsilon-Hcy-Lys-protein autoantibodies was approximately 50% higher than in a group of healthy subjects. CONCLUSIONS: These findings support a hypothesis that Nepsilon-Hcy-Lys-protein is a neoself antigen, which may contribute to immune activation, an important modulator of atherogenesis.