RESUMEN

BACKGROUND: Previously, we reported lower RSK4 mRNA and protein levels in malignant ovarian tumors compared to normal and benign ovarian tissues. Also, we observed a significant inverse correlation between the advanced ovarian cancer stages and RSK4 mRNA levels. We did not investigate the mechanisms involved in RSK4-reduced expression in ovarian cancer. Thus, this study investigates whether RSK4 promoter methylation in ovarian cancer tissues is responsible for its low expression. Additionally, the reactivation of RSK4 expression and its effect was studied in ovarian cancer cell lines. METHODS AND RESULTS: RSK4 promoter methylation percentage in malignant and benign ovarian tumors and normal ovary tissues was determined by combined bisulfite restriction analysis. The reactivation of RSK4 expression by decitabine treatment was studied in OVCAR3, SKOV3, TOV-112D, and TOV-21G cells by Western blotting. Cell proliferation was determined by XTT. A significantly high methylation percentage of the RSK4 promoter was observed among malignant and benign ovarian tumors but not in normal ovarian tissue. RSK4 promoter methylation was not associated with age, histological subtype, or stages of ovarian cancer. RSK4 promoter methylation correlates weakly but not significantly with RSK4 protein expression. No correlation was shown between RSK4 methylation and RSK4 mRNA expression. Decitabine induces RSK4 reactivation in all cell lines. However, cell proliferation was reduced only in TOV-112D cells. CONCLUSION: These data indicate that although RSK4 promoter methylation is increased in malignant ovarian tumors, this mechanism is unlikely to regulate its expression in ovarian cancer. RSK4 reactivation reduced cell proliferation only in the endometroid histological subtype.

Asunto(s)

Neoplasias Ováricas , Proteínas Quinasas S6 Ribosómicas 90-kDa , Femenino , Humanos , Apoptosis , Línea Celular Tumoral , Decitabina/farmacología , Metilación de ADN/genética , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , ARN Mensajero/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Regiones Promotoras Genéticas

RESUMEN

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder in children and adolescents. Although increases in oxidative stress and disturbances of neurotransmitter system such as the dopaminergic and abnormalities in several brain regions have been demonstrated, the pathophysiology of ADHD is not fully understood. Nevertheless, ADHD involves several factors that have been associated with an increase in neuroinflammation. This chapter presents an overview of factors that may increase neuroinflammation and play a potential role in the development and pathophysiology of ADHD. The altered immune response, polymorphisms in inflammatory-related genes, ADHD comorbidity with autoimmune and inflammatory disorders and prenatal exposure to inflammation are associated with alterations in offspring brain development and are a risk factor; genetic and environmental risk factors that may increase the risk for ADHD and medications can increase neuroinflammation. Evidence of an association between these factors has been an invaluable tool for research on inflammation in ADHD. Therefore, evidence studies have made it possible to generate alternative therapeutic interventions using natural products as anti-inflammatories that could have great potential against neuroinflammation in ADHD.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Adolescente , Niño , Femenino , Humanos , Embarazo , Trastorno por Déficit de Atención con Hiperactividad/genética , Encéfalo , Inflamación , Enfermedades Neuroinflamatorias , Factores de Riesgo

RESUMEN

Preeclampsia and intrauterine growth restriction, multisystemic disorders characterized by a shallow trophoblast invasion, have been associated with maternal cadmium (Cd) exposure. The molecular mechanisms of this association remain unknown. Cell adhesion and matrix metalloproteinase production are essential for an adequate trophoblast invasion. Thus, the aim of this study was to determine the effect of Cd exposure on invasion, adhesion, and matrix metalloproteinase-9 (MMP-9) production in the trophoblast-derived HTR-8/SVneo cell line. Cultured HTR-8/SVneo trophoblast cells were incubated with different concentrations of CdCl2 for 6 h. Cell invasion was determined by the transwell assay, while cell adhesion was examined on collagen type I. MMP-9 release and activity were measured by ELISA and zymography, respectively. MMP-9 mRNA expression was detected by reverse-transcription polymerase chain reaction, while intracellular MMP-9 protein was assessed by Western blotting. Cd exposure significantly decreased the invasion and adhesion of HTR-8/SVneo cells. Also, MMP-9 levels and activity in the culture medium were significantly reduced after Cd incubation. In contrast, MMP-9 mRNA expression and intracellular protein levels were significantly increased. These data indicate that Cd reduces trophoblast cells invasiveness by inhibiting cell adhesion and MMP-9 secretion.

Asunto(s)

Cadmio/farmacología , Adhesión Celular/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Trofoblastos/fisiología , Cloruro de Cadmio/administración & dosificación , Línea Celular , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Exposición Materna , Metaloproteinasa 2 de la Matriz/análisis , Metaloproteinasa 2 de la Matriz/genética , Embarazo , ARN Mensajero/análisis , Trofoblastos/efectos de los fármacos

RESUMEN

OBJECTIVE: Recently, a study based on the analysis of accelerated evolution of related genes at birth identified the follicle-stimulating hormone receptor (FSHR) as a possible candidate for the development of preterm delivery. Additionally, FSHR expression has been described in extragonadal tissue including the placenta. Therefore, the aim of the present study was to determine the association between the N680S polymorphism of the follicle-stimulating hormone receptor and preterm birth in a population of Hispanic women. METHODS: Placenta samples were obtained from 64 women who had preterm births and 54 control cases. DNA was extracted and genotyped for the N680S FSHR gene polymorphism by polymerase chain reaction-restriction fragment length polymorphism. The χ2 test and t-test were used to calculate statistical significance. RESULTS: Statistically significant differences in genotype frequencies for the N680S polymorphism were observed between preterm and term groups (p = .04). Based on the Akaike information criterion values, the dominant model showed that the NN genotype had a significantly increased risk of preterm birth compared with the SS + NS genotype (OR 2.52, 95% CI 1.20-5.33, p = .02). CONCLUSIONS: The results herein suggest that the FSHR polymorphism N680S is significantly associated with preterm birth in the Hispanic population.

Asunto(s)

Predisposición Genética a la Enfermedad , Indígenas Centroamericanos/genética , Polimorfismo de Nucleótido Simple , Nacimiento Prematuro/genética , Receptores de HFE/genética , Población Blanca/genética , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Técnicas de Genotipaje , Humanos , México , Embarazo

RESUMEN

Increased levels of matrix metalloproteinase-8 (MMP-8) have been associated with tumor grade and stage in ovarian cancer. Also, it has been reported that higher concentrations of this enzyme in fluid from malignant ovarian cysts compared with benign ovarian cysts. However, no genetic analysis has been conducted yet to assess the contribution of MMP-8 polymorphisms in ovarian cancer. Thus, this study was performed to investigate the frequencies of MMP-8 genotypes in Mexican women with ovarian cancer. MMP-8 promoter genotypes were examined in 35 malignant ovarian tumors, 51 benign tumors, and 37 normal ovary tissues. Two single nucleotide polymorphisms were selected and characterized using polymerase chain reaction-restriction fragment length polymorphism analysis. The chi-square test was used to calculate statistical significance. Haplotype analysis was performed using the SNPstats web tool. Of the two polymorphisms, only the MMP-8 -799 T/T genotype was significantly associated with an increased risk of ovarian cancer (OR 3.78, 95 % CI 1.18-12.13). The Kaplan-Meier analysis for this polymorphism showed that patients with the T/T genetic variant had a tendency toward significant worse overall survival compared with patients with the C/C + C/T genotypes. Haplotype analysis revealed no significant differences in haplotype distribution between benign ovarian tumors, malignant ovarian cancer, and controls. This study suggests that MMP-8 promoter gene polymorphism -799 T/T is significantly associated with an increased risk of ovarian cancer in Mexican women.

Asunto(s)

Metaloproteinasa 8 de la Matriz/genética , Neoplasias Ováricas/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Estimación de Kaplan-Meier , México , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad

RESUMEN

The purpose of this study was to investigate the effect of 1,1,1-trichloro-2,2-bis-(chlorophenyl)ethane (DDT), 1,1-bis-(chlorophenyl)-2,2-dichloroethene (DDE), and 1,1-dichloro-2,2-bis(chlorophenyl)ethane (DDD) isomers on COX-2 expression in a human trophoblast-derived cell line. Cultured HTR-8/SVneo trophoblast cells were exposed to DDT isomers and its metabolites for 24 h, and COX-2 mRNA and protein expression were assessed by RT-PCR, Western blotting, and ELISA. Prostaglandin E2 production was also measured by ELISA. Both COX-2 mRNA and protein were detected under control (unexposed) conditions in the HTR-8/SVneo cell line. COX-2 protein expression and prostaglandin E2 production but not COX-2 mRNA levels increased only after DDE and DDD isomers exposure. It is concluded that DDE and DDD exposure induce the expression of COX-2 protein, leading to increased prostaglandin E2 production. Interestingly, the regulation of COX-2 by these organochlorines pesticides appears to be at the translational level.

Asunto(s)

Carcinógenos Ambientales/toxicidad , Ciclooxigenasa 2/biosíntesis , DDT/toxicidad , Diclorodifenil Dicloroetileno/toxicidad , Diclorodifenildicloroetano/toxicidad , Insecticidas/toxicidad , Trofoblastos/efectos de los fármacos , Carcinógenos Ambientales/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , DDT/análogos & derivados , DDT/metabolismo , Diclorodifenil Dicloroetileno/análogos & derivados , Diclorodifenil Dicloroetileno/metabolismo , Diclorodifenildicloroetano/análogos & derivados , Diclorodifenildicloroetano/metabolismo , Dinoprostona/metabolismo , Inducción Enzimática/efectos de los fármacos , Femenino , Humanos , Insecticidas/química , Insecticidas/metabolismo , Concentración Osmolar , Biosíntesis de Proteínas/efectos de los fármacos , ARN Mensajero/metabolismo , Estereoisomerismo , Trofoblastos/enzimología , Trofoblastos/metabolismo

RESUMEN

OBJECTIVE: Overexpression of progranulin (also named acrogranin, PC-cell-derived growth factor, or granulin-epithelin precursor) is associated with ovarian cancer, specifically with cell proliferation, malignancy, chemoresistance, and shortened overall survival. The objective of the current study is to identify the signaling pathways involved in the regulation of progranulin expression in ovarian cancer cell lines. METHODS: We studied the relation of protein kinase C (PKC), phosphatidylinositol 3-kinase, protein kinase A, P38, extracellular signal-regulated kinase, and Akt pathways on the modulation of progranulin expression levels in NIH-OVCAR-3 and SK-OV-3 ovarian cancer cell lines. The different pathways were examined using pharmacological inhibitors (calphostin C, LY294002, H89, SB203580, PD98059, and Akt Inhibitor), and mRNA and protein progranulin expression were analyzed by reverse transcriptase polymerase chain reaction and Western blot techniques, respectively. RESULTS: Inhibition of PKC signal transduction pathway by calphostin C decreased in a dose-dependent manner protein but not mRNA levels of progranulin in both ovarian cancer cell lines. LY294002 but not wortmannin, which are phosphatidylinositol 3-kinase inhibitors, also diminished the expression of progranulin in both cell lines. In addition, LY294002 treatment produced a significant reduction in cell viability. Inhibition of protein kinase A, P38, extracellular signal-regulated kinase, and Akt did not affect progranulin protein expression. CONCLUSIONS: These results suggest that the PKC signaling is involved in the regulation of progranulin protein expression in 2 different ovarian cancer cell lines. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the cellular proliferation and invasion in ovarian cancer produced by progranulin.

Asunto(s)

Carcinoma/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Ováricas/metabolismo , Proteína Quinasa C/metabolismo , Transducción de Señal , Línea Celular Tumoral , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Regulación hacia Abajo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Progranulinas , Proteína Quinasa C/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

Asunto(s)

Hormona Liberadora de Corticotropina/genética , Nacimiento Prematuro/genética , Femenino , Humanos , México , Polimorfismo Genético , Embarazo , Regiones Promotoras Genéticas , Adulto Joven

RESUMEN

OBJECTIVE: To compare the levels of interleukin (IL)-1beta, IL-6, and matrix metalloproteinase (MMP)-8 in the vaginal secretions of pregnant women with a positive fetal fibronectin (fFN) test result with or without asymptomatic bacterial vaginosis (BV) before and after treatment with oral clindamycin. METHODS: A prospective cohort study was conducted among 43 pregnant women with a positive fFN test result. All patients were treated with clindamycin, and the pre- and post-treatment levels of IL-1beta, IL-6, and MMP-8 were compared. RESULTS: Before treatment, levels of IL-1beta and MMP-8 were significantly higher in women with BV compared with women without BV (P<0.05). Vaginal levels of IL-1beta and IL-6, but not MMP-8, decreased after treatment in pregnant women with BV. CONCLUSIONS: The inability of clindamycin to decrease MMP-8 vaginal levels may explain why it is ineffective in reducing preterm birth in pregnant women with positive fFN and BV.

Asunto(s)

Antibacterianos/farmacología , Clindamicina/farmacología , Metaloproteinasa 8 de la Matriz/efectos de los fármacos , Vaginosis Bacteriana/tratamiento farmacológico , Adulto , Antibacterianos/uso terapéutico , Clindamicina/uso terapéutico , Estudios de Cohortes , Femenino , Fibronectinas/análisis , Humanos , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/metabolismo , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinasa 8 de la Matriz/metabolismo , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/fisiopatología , Nacimiento Prematuro/etiología , Nacimiento Prematuro/prevención & control , Estudios Prospectivos , Vagina/metabolismo , Vagina/microbiología , Vaginosis Bacteriana/complicaciones , Vaginosis Bacteriana/fisiopatología , Adulto Joven

RESUMEN

Human chorionic gonadotropin (hCG) is a placental hormone essential for the maintenance of pregnancy. Previous studies have shown a G to A transition in exon 3 of the hCGbeta gene 5, which changes the naturally occurring valine to methionine in codon 79. The frequency of this transition varies among different ethnic groups, being high in USA women, and less common, or absent, in various European populations. The purpose of the present study was to determine the frequency of the betaV79M allelic variant of the beta-subunit of hCG in a Mexican population, and to compare this frequency with those found in other ethnic groups. Placental DNA from 161 pregnant Mexican women was genotyped for the betaV79M by polymerase chain reaction (PCR)-restriction fragments length polymorphism analysis. No polymorphic betaV79M alleles were identified in the population studied. The allele and genotypic frequencies of betaV79M polymorphism in Mexican Mestizo women were significantly different from those reported for the US population, but not from five different European populations. In contrast to what has been found in women from the USA, it seems that the hCGbeta V79M polymorphism is absent or extremely rare in Mexican Mestizo women.

Asunto(s)

Aborto Espontáneo/genética , Gonadotropina Coriónica Humana de Subunidad beta/genética , Polimorfismo de Nucleótido Simple , Sustitución de Aminoácidos/genética , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Metionina/genética , México , Embarazo , Valina/genética

RESUMEN

OBJECTIVE: To determine whether increased frequency of mutant alleles of the progesterone receptor gene (PGR) was associated with preterm birth in a population of Hispanic women. METHODS: Placental DNA from 64 patients who had preterm births and 54 control patients was genotyped for 4 progesterone receptor gene polymorphisms by polymerase chain reaction (PCR) restriction fragment length polymorphism. The chi(2) test and t test were used to calculate statistical significance. Linkage disequilibrium was calculated using the Linkage Disequilibrium Analyzer program. RESULTS: The genotypic frequencies of the 4 polymorphisms were not significantly different between the study and control groups. In addition, there was complete linkage disequilibrium between V660L, H770H, and PROGINS polymorphisms, but not with +331G/A polymorphism. CONCLUSIONS: The present study suggests that polymorphisms in the progesterone receptor gene are unlikely to be associated with an increased risk of preterm birth in a Hispanic population.

Asunto(s)

Polimorfismo de Longitud del Fragmento de Restricción , Nacimiento Prematuro/genética , Receptores de Progesterona/genética , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Desequilibrio de Ligamiento , México , Placenta , Reacción en Cadena de la Polimerasa , Embarazo

RESUMEN

OBJECTIVE: To compare matrix metalloproteinase (MMP)-8 and MMP-9 levels in the vaginal secretions of pregnant women with or without asymptomatic bacterial vaginosis (BV). METHODS: In this study, vaginal levels and molecular forms of MMP-8 and MMP-9 were studied in 36 pregnant women between 28 and 34 weeks of gestation with asymptomatic BV and 41 pregnant women, matched for gestational age, without BV. RESULTS: Vaginal MMP-8 concentrations were significantly higher (P = .023) in BV-positive women. There was no significant difference in MMP-9 levels between healthy pregnant controls and BV-positive pregnant women. The presence of MMP-8 was confirmed by a 38-kd band on Western blots. CONCLUSIONS: Our findings show that BV is associated with increased levels of MMP-8 in vaginal fluid. Increased production of collagen-degrading enzymes such as MMP-8 is a possible cause of spontaneous preterm delivery in pregnant women with asymptomatic BV.

Asunto(s)

Metaloproteinasas de la Matriz/análisis , Complicaciones Infecciosas del Embarazo/enzimología , Vagina/enzimología , Vaginosis Bacteriana/enzimología , Adulto , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Femenino , Edad Gestacional , Humanos , Metaloproteinasa 8 de la Matriz/análisis , Metaloproteinasa 9 de la Matriz/análisis , Trabajo de Parto Prematuro/enzimología , Paridad , Embarazo