RESUMEN
INTRODUCTION: This study aimed to evaluate the occurrence of clinically relevant (sub)microscopic chromosomal aberrations in fetuses with the nuchal translucency (NT) range from 3.0 to 3.4 mm, which would be potentially missed by cfDNA testing. METHODS: A retrospective data analysis of 271 fetuses with NT between 3.0 and 3.4 mm and increased first trimester combined test (CT) risk in five cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed. RESULTS: A chromosomal aberration was identified in 18.8% fetuses (1:5; 51/271). In 15% (41/271) of cases, trisomy 21, 18, or 13 were found. In 0.7% (2/271) of cases, sex chromosome aneuploidy was found. In 1.1% (3/271) of cases, CNV >10 Mb was detected, which would potentially also be detected by genome-wide cfDNA testing. The residual risk for missing a submicroscopic chromosome aberration in the presented cohorts is 1.8% (1:54; 5/271). CONCLUSION: Our results indicate that a significant number of fetuses with increased CT risk and presenting NT of 3.0-3.4 mm carry a clinically relevant chromosomal abnormality other than common trisomy. Invasive testing should be offered, and counseling on NIPT should include the test limitations that may result in NIPT false-negative results in a substantial percentage of fetuses.
RESUMEN
Preeclampsia (PE) is a unique pregnancy disorder affecting women across the world. It is characterized by the new onset of hypertension with coexisting end-organ damage. Although the disease has been known for centuries, its exact pathophysiology and, most importantly, its prevention remain elusive. The basis of its associated molecular changes has been attributed to the placenta and the hormones regulating its function. One such hormone is chromogranin A (CgA). In the placenta, CgA is cleaved to form a variety of biologically active peptides, including catestatin (CST), known inter alia for its vasodilatory effects. Recent studies indicate that the CST protein level is diminished both in patients with hypertension and those with PE. Therefore, the aim of the present paper is to review the most recent and most relevant in vitro, in vivo, and clinical studies to provide an overview of the proposed impact of CST on the molecular processes of PE and to consider the possibilities for future experiments in this area.
Asunto(s)
Hipertensión , Preeclampsia , Humanos , Femenino , Cromogranina A/metabolismo , Fragmentos de Péptidos/metabolismoRESUMEN
Pregnancy is a state of physiological and hormonal changes. One of the endocrine factors involved in these processes is chromogranin A, an acidic protein produced, among others, by the placenta. Although it has been previously linked to pregnancy, no existing articles have ever managed to clarify the role of this protein regarding this subject. Therefore, the aim of the present study is to gather knowledge of chromogranin A's function with reference to gestation and parturition, clarify elusive information, and, most importantly, to formulate hypotheses for the future studies to verify.
Asunto(s)
Cromograninas , Sistema Endocrino , Embarazo , Femenino , Humanos , Cromogranina A/metabolismo , Cromograninas/metabolismo , Sistema Endocrino/metabolismo , Parto , Placenta/metabolismo , Fragmentos de Péptidos/metabolismoRESUMEN
One of the most dangerous complications of pregnancy is preeclampsia (PE), a disease associated with a high risk of maternal and fetal mortality and morbidity. Although its etiology remains unknown, the placenta is believed to be at the center of ongoing changes. One of the hormones produced by the placenta is chromogranin A (CgA). Thus far, its role in pregnancy and pregnancy-related disorders is enigmatic, yet it is known that both CgA and its derived peptide catestatin (CST) are involved in the majority of the processes that are disturbed in PE, such as blood pressure regulation or apoptosis. Therefore, in this study, the influence of the preeclamptic environment on the production of CgA using two cell lines, HTR-8/SVneo and BeWo, was investigated. Furthermore, the capacity of trophoblastic cells to secrete CST to the environment was tested, as well as the correlation between CST and apoptosis. This study provided the first evidence that CgA and CST proteins are produced by trophoblastic cell lines and that the PE environment has an impact on CST protein production. Furthermore, a strong negative correlation between CST protein level and apoptosis induction was found. Hence, both CgA and its derived peptide CST may play roles in the complex process of PE pathogenesis.
Asunto(s)
Preeclampsia , Embarazo , Femenino , Humanos , Preeclampsia/metabolismo , Trofoblastos/metabolismo , Placenta/metabolismo , Línea Celular , Presión SanguíneaRESUMEN
Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no "key players" regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods.
Asunto(s)
Preeclampsia , Embarazo , Femenino , Humanos , Preeclampsia/prevención & control , Preeclampsia/diagnóstico , Cesárea , Placentación , Estrés Oxidativo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Preeclampsia (PE) is characterised by high levels and activity of the transcription factor Nuclear Factor kappa B (NFĸB) in the maternal blood and placental cells. This factor is responsible for the regulation of over 400 genes known to influence processes related to inflammation, apoptosis and angiogenesis, and cellular responses to oxidative stress and hypoxia. Although high NFĸB activity induces hypoxia and inflammation, which are beneficial for the process of implantation, NFĸB level should be reduced in the later stages of physiological pregnancy to favour maternal immunosuppression and maintain gestation. It is believed that the downregulation of NFĸB activity by pharmacotherapy might be a promising way to treat preeclampsia. Interestingly, many of the drugs adopted for the prevention and treatment of preeclampsia have been found to regulate NFĸB activity. Despite this, further innovation is urgently needed to ensure treatment safety and efficacy. The present article summarizes the current state of knowledge about the drugs recommended by cardiology, obstetrics, and gynaecology societies for the prevention and treatment of preeclampsia with regard to their impact on the cellular regulation of NFĸB pathways.
Asunto(s)
Preeclampsia , Femenino , Humanos , Hipoxia/metabolismo , Inflamación/metabolismo , FN-kappa B/metabolismo , Placenta/metabolismo , Preeclampsia/tratamiento farmacológico , Preeclampsia/metabolismo , Preeclampsia/prevención & control , EmbarazoRESUMEN
In vivo studies on the pathology of gestation, including preeclampsia, often use small mammals such as rabbits or rodents, i.e., mice, rats, hamsters, and guinea pigs. The key advantage of these animals is their short reproductive cycle; in addition, similar to humans, they also develop a haemochorial placenta and present a similar transformation of maternal spiral arteries. Interestingly, pregnant dams also demonstrate a similar reaction to inflammatory factors and placentally derived antiangiogenic factors, i.e., soluble fms-like tyrosine kinase 1 (sFlt-1) or soluble endoglin-1 (sEng), as preeclamptic women: all animals present an increase in blood pressure and usually proteinuria. These constitute the classical duet that allows for the recognition of preeclampsia. However, the time of initiation of maternal vessel remodelling and the depth of trophoblast invasion differs between rabbits, rodents, and humans. Unfortunately, at present, no known animal replicates a human pregnancy exactly, and hence, the use of rabbit and rodent models is restricted to the investigation of individual aspects of human gestation only. This article compares the process of placentation in rodents, rabbits, and humans, which should be considered when planning experiments on preeclampsia; these aspects might determine the success, or failure, of the study. The report also reviews the rodent and rabbit models used to investigate certain aspects of the pathomechanism of human preeclampsia, especially those related to incorrect trophoblast invasion, placental hypoxia, inflammation, or maternal endothelial dysfunction.
Asunto(s)
Preeclampsia , Conejos , Femenino , Embarazo , Humanos , Ratones , Ratas , Cobayas , Animales , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Placenta/irrigación sanguínea , Roedores , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Although preeclampsia has long been recognized as a condition affecting late pregnancy, little is known of its pathogenesis or treatment. The placenta releases a number of hormones and molecules that influence the course of pregnancy, one of which is chromogranin A, a soluble protein secreted mainly from the chromaffin cells of the adrenal medulla. Its role in pregnancy and pregnancy-related disorders remains unclear. Therefore, the main aim of the proposed study is to determine whether chromogranin A is related with the occurrence of preeclampsia. METHODS: Placental samples were collected from 102 preeclamptic patients and 103 healthy controls, and Chromogranin A gene (CHGA) expression was measured using real-time RT-PCR, The RT-PCR results were verified on the protein level using ELISA. The normal distribution of the data was tested using the Shapiro-Wilk test. The clinical and personal characteristics of the groups were compared using the Student's t-test for normally-distributed data, and the χ2 test for categorical variables. The Mann-Whitney U test was used for non-normally distributed data. As the log- transformation was not suitable for the given outcomes, the Box- Cox Transformation was used to normalize data from ELISA tests and CHGA expression. Values of P < .05 were considered statistically significant. RESULTS: Chromogranin A gene expression was found to be significantly higher in the study group than in controls. Protein analyses showed that although the CgA concentration in placental samples did not differ significantly, the catestatin (CST) level was significantly lower in samples obtained from women with preeclampsia, according to the controls. CONCLUSIONS FOR PRACTICE: This study for the first time reveals that chromogranin A gene expression level is associated with preeclampsia. Moreover, the depletion in catestatin level, which plays a protective role in hypertension development, might be a marker of developing preeclampsia. Further studies may unravel role of Chromogranin A in the discussed disease.
Asunto(s)
Cromogranina A/metabolismo , Fragmentos de Péptidos/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Biomarcadores/metabolismo , Estudios de Casos y Controles , Cromogranina A/genética , Femenino , Expresión Génica , Humanos , Fragmentos de Péptidos/genética , Preeclampsia/genética , EmbarazoRESUMEN
Preeclampsia is a pregnancy disorder associated with shallow placentation, forcing placental cells to live in hypoxic conditions. This activates the transcription factor kappa B (NFκB) in maternal and placental cells. Although the role of NFκB in preeclampsia is well documented, its mechanism of activation in trophoblastic cells has been never studied. This study investigates the mechanism of NFκB activation in a first trimester trophoblastic cell line (HTR8/SVneo) stimulated by a medium containing serum from preeclamptic (PE) or normotensive (C) women in hypoxic (2% O2) or normoxic (8% O2) conditions. The results indicate that in HTR8/SVneo cells, the most widely studied NFκB pathways, i.e., canonical, non-canonical and atypical, are downregulated in environment PE 2% O2 in comparison to C 8% O2. Therefore, other pathways may be responsible for NFκB activation. One such pathway depends on the activation of NFκB by the p53/RSK1 complex through its phosphorylation at Serine 536 (pNFκB Ser536). The data generated by our study show that inhibition of the p53/RSK1 pathway by p53-targeted siRNA results in a depletion of pNFκB Ser536 in the nucleus, but only in cells incubated with PE serum at 2% O2. Thus, the p53/RSK1 complex might play a critical role in the activation of NFκB in trophoblastic cells and preeclamptic placentas.
Asunto(s)
FN-kappa B/metabolismo , Preeclampsia/patología , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Trofoblastos/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Hipoxia de la Célula/fisiología , Línea Celular , Activación Enzimática/genética , Femenino , Humanos , Placenta/patología , Embarazo , Interferencia de ARN , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a rare disease, triggered by defective GnRH secretion, that is usually diagnosed in late adolescence or early adulthood due to the lack of spontaneous pubertal development. To date more than 30 genes have been associated with CHH pathogenesis with X-linked recessive, autosomal dominant, autosomal recessive and oligogenic modes of inheritance. Defective sense of smell is present in about 50-60% of CHH patients and called Kallmann syndrome (KS), in contrast to patients with normal sense of smell referred to as normosmic CHH. ANOS1 and FGFR1 genes are all well established in the pathogenesis of CHH and have been extensively studied in many reported cohorts. Due to rarity and heterogenicity of the condition the mutational spectrum, even in classical CHH genes, have yet to be fully characterized. METHODS: To address this issue we screened for ANOS1 and FGFR1 variants in a cohort of 47 unrelated CHH subjects using targeted panel sequencing. All potentially pathogenic variants have been validated with Sanger sequencing. RESULTS: Sequencing revealed two ANOS1 and four FGFR1 mutations in six subjects, of which five are novel and one had been previously reported in CHH. Novel variants include a single base pair deletion c.313delT in exon 3 of ANOS1, three missense variants of FGFR1 predicted to result in the single amino acid substitutions c.331C > T (p.R111C), c.1964 T > C (p.L655P) and c.2167G > A (p.E723K) and a 15 bp deletion c.374_388delTGCCCGCAGACTCCG in exon 4 of FGFR1. Based on ACMG-AMP criteria reported variants were assigned to class 5, pathogenic or class 4, likely pathogenic. Protein structural predictions, the rarity of novel variants and amino acid conservation in case of missense substitutions all provide strong evidence that these mutations are highly likely to be deleterious. CONCLUSIONS: Despite the fact that ANOS1 and FGFR1 are classical CHH genes and were thoroughly explored in several CHH cohorts we identified new, yet undescribed variants within their sequence. Our results support the genetic complexity of the disorder. The knowledge of the full genetic spectrum of CHH is increasingly important in order to be able to deliver the best personalised medical care to our patients.
Asunto(s)
Proteínas de la Matriz Extracelular/genética , Hipogonadismo/genética , Síndrome de Kallmann/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Adolescente , Secuencia de Aminoácidos , Femenino , Variación Genética/genética , Humanos , Hipogonadismo/diagnóstico , Síndrome de Kallmann/diagnóstico , MasculinoRESUMEN
Although higher nuclear factor κB (NFκB) expression and activity is observed in preeclamptic placentas, its mechanism of activation is unknown. This is the first study to investigate whether the canonical, non-canonical, or atypical NFκB activation pathways may be responsible for the higher activation of NFκB observed in preeclamptic placentas. The study included 268 cases (130 preeclamptic women and 138 controls). We studied the expression of the genes coding for NFκB activators (NIK, IKKα, IKKß, and CK2α) and inhibitors (IκBα and IκBß) using RT-PCR in real time. The RT-PCR results were verified on the protein level using ELISA and Western blot. To determine the efficiency of the pathways, the ratios of activator(s) to one of the inhibitors (IκBα or IκBß) were calculated for each studied pathway. The preeclamptic placentas demonstrated significantly lower IKKα and CK2α but higher IκBα and IκBß protein levels. In addition, the calculated activator(s) to inhibitor (IκBα or IκBß) ratios suggested that all studied pathways might be downregulated in preeclamptic placentas. Our results indicate that preeclamptic placentas may demonstrate mechanisms of NFκB activation other than the canonical, non-canonical, and atypical forms. In these mechanisms, inhibitors of NFκB may play a key role. These observations broaden the existing knowledge regarding the molecular background of preeclampsia development.
Asunto(s)
Quinasa I-kappa B/genética , Preeclampsia/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Núcleo Celular/genética , Femenino , Regulación de la Expresión Génica/genética , Humanos , FN-kappa B/genética , Placenta/metabolismo , Placenta/patología , Preeclampsia/patología , Embarazo , Transducción de Señal/genética , Quinasa de Factor Nuclear kappa BRESUMEN
A linkage of dichorionic (DC) twin pregnancies with selective intrauterine growth restriction (IUGR) to alterations in placental gene expression is unclear. The aim of the study was to identify placental genes related to hypoxia, adipogenesis and human growth which may contribute to IUGR development. The study group (IUGR/AGA) comprised dichorionic (DC) twin pregnancies, where the weight of the twins differed by > 15%; in addition, one twin was small for gestational age (< 10th percentile-SGA) (IUGR) while the other was appropriate for gestational age (> 10th percentile-AGA). In the control group (AGA/AGA), both fetuses were AGA and their weights differed by < 15%. In the first step (selection), placental expression of 260 genes was analysed by commercial PCR profiler array or qPCR primer assay between six pairs of IUGR/AGA twins. In the second stage (verification), the expression of 20 genes with fold change (FC) > 1.5 selected from the first stage was investigated for 75 DC pregnancies: 23 IUGR/AGA vs. 52 AGA/AGA. The expression of Angiopoetin 2, Leptin and Kruppel-like factor 4 was significantly higher, and Glis Family Zinc Finger 3 was lower, in placentas of SGA fetuses (FC = 3.3; 4.4; 1.6; and - 1.8, respectively; p < 0.05). The dysregulation of gene expression related to angiogenesis and growth factors in placentas of twins born from IUGR/AGA pregnancies suggest that these alternations might represent biological fetal adaptation to the uteral condition. Moreover, DC twin pregnancies may be a good model to identify the differences in placental gene expression between SGA and AGA fetuses.
Asunto(s)
Retardo del Crecimiento Fetal/genética , Perfilación de la Expresión Génica/métodos , Placenta/metabolismo , Embarazo Gemelar/genética , Proteínas de Unión al ADN , Femenino , Edad Gestacional , Humanos , Hipoxia , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Embarazo , Proteínas Represoras , Transactivadores , Factores de Transcripción/genéticaRESUMEN
Zearalenone (ZEA) - a fungal mycotoxin is reported to both cause the oxidative stress associated with death of cells as well as induction of the proliferation of cells, depending on its concentration and the type of cells. ZEA due to its structural similarity to naturally occurring estrogens is able to bind to estrogen receptors and triggers estrogen-associated signaling pathways. The aim of this study is to evaluate whether the induction of oxidative stress in normal epithelial prostate PNT1A cells is associated with estrogenic activity of ZEA. We observed that ZEA-induced oxidative stress in PNT1A cells is associated with a decrease in the oxidative stress defense enzymes expression, cell cycle arrest in G2/M cell cycle phase as well as the decreased migration of cells. The results also suggest that the observed effect might be associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)- hypoxia inducible factor 1 alpha (HIF-1α) signaling pathway. The usage of estrogen receptor ß (ERß) selective antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-phenol PHTPP showed that ERß activity is able to decrease the ZEA-induced oxidative stress, but is not enough to counteract it, indicating that ZEA-induced oxidative stress is only partially associated with estrogenic activity of ZEA.
Asunto(s)
Puntos de Control del Ciclo Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Receptor beta de Estrógeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Próstata/citología , Zearalenona/toxicidad , Catalasa/metabolismo , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Epiteliales/metabolismo , Estrógenos/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , FN-kappa B/metabolismo , Próstata/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
INTRODUCTION: The aim of this study was to analyse a panel of 60 angiogenic factors (pro-angiogenic and antiangiogenic) in the plasma of women with mild preeclampsia. MATERIALS AND METHODS: We recruited 21 women between 25 and 40 weeks gestation with diagnosed mild preeclampsia into the study group and 27 healthy women with uncomplicated pregnancies of corresponding gestational age to that of the study to the control group. We used a quantitative protein macroarray method that allowed for analysis of 60 angiogenic proteins per sample simultaneously. RESULTS: We showed a statistically significant increase in the concentration of 8 proteins, interferon gamma (IFN-γ), interleukin 6 (IL-6), leukaemia inhibitory factor (LIF), heparin-binding EGF-like growth factor (HB-EGF), hepatocyte growth factor (HGF), C-X-C motif chemokine 10 (IP-10), leptin and platelet-derived growth factor BB (PDGF-BB), as well as a significant decrease in the concentration of 3 proteins, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and follistatin, in the plasma of women with preeclampsia. CONCLUSION: Based on our findings, it seems that protein factors may play an important role in the pathogenesis of preeclampsia, and there are many proteins that have not been studied in PE to date. There are no previous studies assessing the LIF, follistatin, HGF, HB-EGF and PDGF-BB concentrations in the plasma of women with PE; therefore, our obtained results indicate that these proteins are new factors that can play an important role in the pathomechanisms of PE.
Asunto(s)
Inductores de la Angiogénesis/sangre , Preeclampsia/sangre , Preeclampsia/diagnóstico , Proteínas Gestacionales/sangre , Adulto , Femenino , Humanos , Embarazo , Reproducibilidad de los ResultadosRESUMEN
PURPOSE OF REVIEW: Preeclampsia (PE) is a hypertensive disorder exclusive for pregnancy. It affects women all over the world and poses a great threat to life, both for mother and child. No definitive treatment exists and placenta delivery comprises the only known cure for PE. One of the most severe complications observed in preeclamptic women is the occurrence of cardiovascular diseases (CVDs) later in life. RECENT FINDINGS: Both PE and CVDs share some of their pathogenic pathways and gene variations. Thus far, a number of publications have examined those relationships; however, almost all of them focus only on common risk factors. The precise pathomechanism and genetic basis of PE and its associated cardiovascular complications remain unknown. Therefore, the aim of this review is to unify and clarify the current state of knowledge and provide direction for future studies, especially those regarding the genetic aspect.
Asunto(s)
Enfermedades Cardiovasculares , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Femenino , Antecedentes Genéticos , Humanos , Preeclampsia/genética , Preeclampsia/metabolismo , Preeclampsia/fisiopatología , Embarazo , Factores de RiesgoRESUMEN
BACKGROUND: The mechanism of preeclampsia and its way of inheritance are still a mystery. Biochemical and immunochemical studies reveal a substantial increase in tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 concentrations in the blood of women with preeclampsia. The level of these factors is regulated by nuclear facxtor-kappa B, whose activation in a classical pathway requires inhibitory kappa B kinase gamma (known as NEMO or IKBKG). Moreover, NEMO can schedule between cytoplasma and the nucleus. In the nucleus, IKBKG interacts with other proteins, and thus, it is implicated in the regulation of different gene expressions, which are related to cell cycle progression, proliferation, differentiation, and apoptosis. OBJECTIVE: This is the first study investigating the association between the level of NEMO gene expression and the presence of preeclampsia. We tested the hypothesis that the simultaneous increase in NEMO gene expression both in the mother and her fetus may be responsible for the preeclampsia development. Moreover, the relationships between clinical risk factors of preeclampsia and the levels of NEMO gene expression in blood, umbilical cord blood, and placentas were investigated. STUDY DESIGN: A total of 91 women (43 preeclamptic women and 48 controls) and their children were examined. Real-time reverse transcription-polymerase chain reaction was used to assess the amount total NEMO messenger ribonucleic acid (mRNA) content and the mRNA level of each NEMO transcript from exons 1A, 1B, and 1C in maternal blood, umbilical cord blood, and placentas. Univariate analyses and correlation tests were performed to examine the association between NEMO gene expression and preeclampsia. RESULTS: Newborn weight and height, maternal platelet number, and gestational age (week of delivery) were lower in the group of women with preeclampsia than controls. NEMO gene expression level was found to be almost 7 times higher in the group of women with preeclampsia than healthy controls. The correlation analysis found that a simultaneous increase in the expression level of total NEMO mRNA in maternal blood and the mRNA for total NEMO (Rs = 0.311, P < .05), transcripts 1A (Rs = 0.463, P < .01), 1B (Rs = 0.454, P < .01), and 1C (Rs = 0.563, P < .001) in fetal blood was observed in preeclamptic pregnancies. In addition, the mRNA levels for total NEMO and transcripts 1A, 1B, and 1C were lower in placentas derived from pregnancies complicated by preeclampsia. CONCLUSION: Simultaneous increase of NEMO gene expression in maternal and fetal blood seems to be relevant for preeclampsia development. The results of our study also suggest that a decreased NEMO gene expression level in preeclamptic placentas may be the main reason for their intensified apoptosis.
Asunto(s)
Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Preeclampsia/sangre , Preeclampsia/genética , ARN Mensajero/metabolismo , Adulto , Biomarcadores/metabolismo , Estudios de Casos y Controles , Femenino , Sangre Fetal/metabolismo , Expresión Génica , Humanos , Placenta/metabolismo , Reacción en Cadena de la Polimerasa , Embarazo , Transcripción GenéticaRESUMEN
BACKGROUND: Essential hypertension (EH) is the most common cardiovascular disease worldwide, and it has a strong genetic component. Cortisol homeostasis is an important factor in controlling blood pressure, and the availability of this hormone is regulated by 11ßhydroxysteroid dehydrogenase type 1 enzyme (11ßHSD1), which converts cortisone into cortisol. MATERIALS AND METHODS: We investigated the correlation between EH and the single nucleotide polymorphism (SNP) ins4436A located on the hydroxysteroid (11-beta) dehydrogenase 1 gene among the Polish population. The study included a total of 268 patients with confirmed EH and 151 unrelated controls. All studied polymorphisms were detected using the restriction fragment length polymorphism (RFLP) method. RESULTS: The carriage of ins4436A (rs45487298) polymorphism in intron 3 of the HSD11B1 gene was more frequent among patients with EH than among controls (p=0.013). The analysis of association of ins4436A with the risk of EH indicated an odds ratio (OR) of 2.44 (95% confidential interval: 1.24-4.82). Moreover, essential hypertension occurred less frequently in males than in females. Results of multivariate analysis in the study group showed that ins4436A is a strong predictor of diabetes mellitus type 2 and ins4436A may lead to a decrease of the high-density lipoprotein (HDL) cholesterol level. DISCUSSION: The cause of essential hypertension has not been fully established, but genetic factors seem to play a very important role. In our study we found that ins4436A in the HSD11B1 gene was associated with essential hypertension in a Polish population. Nevertheless, the impact of ins4436A in the HSD11B1 gene on the occurrence of essential hypertension requires further investigations.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Predisposición Genética a la Enfermedad , Hipertensión/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Anciano , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/genética , Hipertensión Esencial , Femenino , Humanos , Hipertensión/enzimología , Masculino , Persona de Mediana Edad , Polonia , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Retinal ganglion cells (RGCs), neurons transmitting visual information via the optic nerve, fail to regenerate their axons after injury. The progressive loss of RGC function underlies the pathophysiology of glaucoma and other optic neuropathies, often leading to irreversible blindness. Therefore, there is an urgent need to identify the regulators of RGC survival and the regenerative program. In this study, we investigated the role of the family of transcription factors known as nuclear factor of activated T cells (NFAT), which are expressed in the retina; however, their role in RGC survival after injury is unknown. Using the optic nerve crush (ONC) model, widely employed to study optic neuropathies and central nervous system axon injury, we found that NFATc4 is specifically but transiently up-regulated in response to mechanical injury. In the injured retina, NFATc4 immunolocalized primarily to the ganglionic cell layer. Utilizing NFATc4-/- and NFATc3-/- mice, we demonstrated that NFATc4, but not NFATc3, knockout increased RGC survival, improved retina function, and delayed axonal degeneration. Microarray screening data, along with decreased immunostaining of cleaved caspase-3, revealed that NFATc4 knockout was protective against ONC-induced degeneration by suppressing pro-apoptotic signaling. Finally, we used lentiviral-mediated NFATc4 delivery to the retina of NFATc4-/- mice and reversed the pro-survival effect of NFATc4 knockout, conclusively linking the enhanced survival of injured RGCs to NFATc4-dependent mechanisms. In summary, this study is the first to demonstrate that NFATc4 knockout may confer transient RGC neuroprotection and decelerate axonal degeneration after injury, providing a potent therapeutic strategy for optic neuropathies.
RESUMEN
PURPOSE: The excessive fructose intake including high-fructose corn syrup (HFCS) may be responsible for increase of obesity occurrence. This study was designed to find potential differences in duodenal fructose transporters on mRNA and protein levels between obese and normal weight children and adolescents. MATERIALS/METHODS: We performed a cross-sectional study on a group of 106 hospitalized patients aged 12 to 18. Glucose transporter 2 (GLUT2) and glucose transporter 5 (GLUT5) mRNA as well as protein levels (ELISA and Western blot methods) were assessed in duodenal mucosa biopsies of the patients categorized as obese or normal weight. Additionally, the expression of the aforementioned transporters was analyzed in patients based on the presence of insulin resistance (IR) and metabolic syndrome (MS). RESULTS: In children with obesity, increased duodenal protein levels of GLUT5 (Relative protein GLUT5 expression/ACTB) (0.027 â± â0.009 vs. 0.011 â± â0.006, p â< â0.05) but not GLUT2 as compared with the normal weight group, were revealed. No significant differences in duodenal relative GLUT2 and GLUT5 genes expression between the studied groups were found. There was no relationship between the presence of IR or MS and intestinal mRNA GLUT2 and GLUT5 as well as GLUT2 protein expression. CONCLUSION: The upregulation of the duodenal GLUT5 may contribute to obesity occurrence in children and adolescents.
RESUMEN
Background: The prevalence of long-COVID (LC) presents a significant challenge to healthcare systems globally. There are still some discrepancies on the role of sex as an independent risk factor of LC complications. Thus, we aimed to determine the differences in clinical and cardiovascular complications between males and females without comorbidities after COVID-19. Methods: Clinical data on the course of the disease with the accompanying symptoms and post-COVID-19 symptoms were compiled from both male and female subjects with a minimum 12-week interval after COVID-19 recovery. Next, the patients were followed for 12 months. ECG, echocardiography, 24 h ECG monitoring, 24 h ambulatory blood pressure monitoring (ABPM), and selected biochemical tests were performed. LC was diagnosed based on the World Health Organization (WHO) definition. To reduce the impact of confounders, i.e., body mass index (BMI) and age, on the results of the study, the nearest neighbour (NN) propensity score matching (PSM) method with a 1:1 ratio was used. Results: The results were obtained following the removal of cases with comorbidities from the database consisting of 1237 males and 2192 females, and PSM of the new database included 886 cases (443 males and 443 females). At both the 3-month and 1-year post-recovery marks, females consistently reported a higher frequency of LC symptoms compared to males (p < 0.001 for both comparisons). Moreover, after 1 year of follow-up, females exhibited a higher prevalence of LC compared to males, with rates of 14% versus 8.3%, respectively (p = 0.013). The symptoms that significantly differed between females and males in the 12-month follow-up were hair loss (5.4 vs. 0.7%, p < 0.001), memory and concentration disturbances (8.4 vs. 4.3%, p = 0.013), and headaches (4.3 vs. 1.4%, p = 0.008). Females presented lower mean arterial pressure (MAP) [89 (83-95) mmHg versus (vs.) 94 (89-100); p < 0.001] and lower pulse pressure (PP) [46 (42-52) mmHg vs. 51 (48-57); p < 0.001] in 24 h ABPM and more elevated heart rates (HRs) in 24 h ECG monitoring as well as arrhythmia (p < 0.001 and p = 0.018, respectively). Males had a higher occurrence of ECG abnormalities such as QRS >= 120 ms, ST-T changes, T inversion, arrhythmia, and QRS fragmentation (27.3% vs. 19.2%; p = 0.004). No significant differences were observed between males and females concerning physical activity levels, stress, fatigue, alcohol consumption, and smoking habits. Conclusions: One year post-COVID-19 recovery, regardless of age and BMI, healthy females more often suffered from LC symptoms than males. They had lower MAP and PP in 24 h ABPM, more often had higher HRs and arrhythmia in 24 h ECG monitoring, and fewer ECG abnormalities than males.