Diagnostic Potential of Exosomal HypoxamiRs in the Context of Hypoxia–Sumoylation–HypoxamiRs in Early Onset Preeclampsia at the Preclinical Stage

As the search for non-invasive preclinical markers of preeclampsia (PE) expands, the number of studies on the diagnostic potential of exosomes is growing. Changes in the partial pressure of oxygen caused by impaired uteroplacental perfusion in PE are a powerful inducer of increased production and release of exosomes from cells, which also determine their cargo. At the same time, the expression pattern of oxygen-dependent microRNAs (miRNAs), called “hypoxamiRs”, is modulated, and their packing into exosomes is strictly regulated by sumoylation. In connection therewith, we emphasize the evaluation of exosomal hypoxamiR expression (miR-27b-3p, miR-92b-3p, miR-181a-5p, and miR-186-5p) using quantitative RT-PCR, as well as SUMO 1–4 and UBC9 (by Western blotting), in pregnant women with early-onset PE. The findings show that miR-27b-3p and miR-92b-3p expression was significantly changed at 11–14 and 24–26 weeks of gestation in the blood plasma of pregnant women with early-onset PE, which subsequently manifested. High sensitivity and specificity (AUC = 1) were demonstrated for these miRNAs in the first trimester, and significant correlations with a decrease in hemoglobin (r = 0.71, p = 0.002; r = −0.71, p = 0.002) were established. In mid-pregnancy, the miR-27b-3p expression was found to correlate with an increase in platelets (r = −0.95, p = 0.003), and miR-92b-3p was associated with a decrease in the prothrombin index (r = 0.95, p = 0.003). Specific exomotifs of studied miRNAs were also identified, to which the sumoylated ribonucleoprotein hnRNPA2/B1 binds, carrying out their packaging into exosomes. The expression of conjugated SUMO 1 (p = 0.05), SUMO 2/3/4 (p = 0.03), and UBC9 (p = 0.1) was increased in exosomes at early-onset PE, and the expression of free SUMO 1 (p = 0.03) and SUMO 2/3/4 (p = 0.01) was significantly increased in the placenta, as an adaptive response to hypoxia. Moreover, SUMO 2/3/4 was negatively correlated with miR-27b-3p expression in the placenta. In conclusion, the diagnostic potential of exosomal hypoxamiRs mediated by sumoylation may form the basis for the development of combined specific targets for the treatment of early-onset PE, as hnRNPA2/B1 is a target of miR-27b-3p, and its sumoylation creates miR-27b-3p–hnRNPA2/B1–SUMO 1–4 cross-talk.

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Prediction of preeclampsia using a combination of serum micro RNA-210 and uterine artery Doppler ultrasound

Science Progress ◽

10.1177/00368504211036856 ◽

2021 ◽

Vol 104 (3) ◽

pp. 003685042110368

Author(s):

Ananya Trongpisutsak ◽

Vorapong Phupong

Keyword(s):

Pregnant Women ◽

Doppler Ultrasound ◽

Predictive Value ◽

Early Onset ◽

Uterine Artery ◽

Micro Rna ◽

Predictive Values ◽

Uterine Artery Doppler ◽

Early Onset Preeclampsia ◽

Sensitivity Specificity

The objective was to determine whether a combination of serum micro RNA-210 level and uterine artery Doppler can predict preeclampsia in pregnant women at 16–24 weeks gestation. A prospective observational study conducted in singleton pregnant women at 16–24 weeks of gestation who had prenatal care at the King Chulalongkorn Memorial Hospital, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand between 2017 and 2018. Uterine artery Doppler ultrasound and blood testing for serum micro RNA-210 were performed. Pregnancy outcomes were recorded. Optimal cut-off for uterine artery pulsatility index (PI) and serum micro RNA-210 were obtained to calculate the predictive values for preeclampsia. Data from 443 participants were analyzed. Twenty-two cases developed preeclampsia (5.0%) and seven of these preeclamptic cases had early-onset preeclampsia (1.6%). Pregnant women with preeclampsia had higher mean PI of the uterine artery (1.34 ± 0.52 vs 0.98 ± 0.28, p = 0.004), higher detection rates of diastolic notching (45.5% vs 11.2%, p < 0.001), and lower median serum micro RNA-210 level (22.86 vs 795.78, p < 0.001) than pregnant women without preeclampsia. Using abnormal serum micro RNA-210 level, abnormal mean PI or uterine artery diastolic notches to predict for preeclampsia, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 95.5%, 54.9%, 10.0%, and 99.6%, respectively. For early-onset preeclampsia prediction, the sensitivity, specificity, PPV, and NPV were 100.0%, 53.2%, 3.3%, and 100.0%, respectively. This study demonstrated that a combination of serum micro RNA-210 and uterine artery Doppler is effective in predicting preeclampsia in the second trimester.

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Altered Maternal Serum Matrix Metalloproteinases MMP-2, MMP-3, MMP-9, and MMP-13 in Severe Early- and Late-Onset Preeclampsia

BioMed Research International ◽

10.1155/2017/6432426 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 15

Author(s):

Marzena Laskowska

Keyword(s):

Matrix Metalloproteinases ◽

Pregnant Women ◽

Immunosorbent Assay ◽

Early Onset ◽

Late Onset ◽

Maternal Serum ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Controls ◽

Control Subjects ◽

Early Onset Preeclampsia

Objective. The aim of this study was to determine whether maternal serum matrix metalloproteinases 2, 3, 9, and 13 levels differ in early- and late-onset preeclampsia and uncomplicated pregnancies. Patients and Methods. The study was carried out in 125 pregnant women (29 with early-onset preeclampsia; 31 preeclamptic patients with late-onset preeclampsia; and 65 healthy pregnant controls). Levels of MMP-2, MMP-3, MMP-9, and MMP-13 were measured in the maternal serum using an enzyme-linked immunosorbent assay. Results. Maternal serum MMP-2 levels in both the groups of preeclamptic women were significantly higher than those in the controls. Levels of MMP-3 were significantly higher in preeclamptic patients with early-onset disease; however, the MMP-3 levels in patients with late-onset preeclampsia were similar to those observed in the control subjects. MMP-9 levels were lower whereas the levels of MMP-13 were higher in both preeclamptic groups of pregnant women than in the healthy controls, but these differences were statistically insignificant. Conclusions. One important finding of the present study was that MMP-3 appears to be involved solely in early-onset preeclampsia, but not in late-onset preeclampsia. Higher levels of MMP-2 and MMP-13 and lower levels of MMP-9 seem to be related to both early- and late-onset severe preeclampsia.

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269: Association between severe early onset preeclampsia (PE) and serum measures of first trimester pregnancy associated plasma protein A (PAPP-A) and human chorionic gonadotrophin (hCG)

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2013.10.302 ◽

2014 ◽

Vol 210 (1) ◽

pp. S143

Author(s):

Laura Jelliffe ◽

Maurice Druzin ◽

Rebecca Baer ◽

Deirdre Lyell ◽

Yasser El-Sayed ◽

...

Keyword(s):

Plasma Protein ◽

Early Onset ◽

Protein A ◽

First Trimester ◽

Chorionic Gonadotrophin ◽

Human Chorionic Gonadotrophin ◽

First Trimester Pregnancy ◽

Trimester Pregnancy ◽

Early Onset Preeclampsia

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HtrA3 Isoform–Specific ELISAs for Early Detection of Preeclampsia

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/1087057116682425 ◽

2016 ◽

Vol 23 (10) ◽

pp. 1092-1099 ◽

Cited By ~ 2

Author(s):

Yao Wang ◽

Ying Li ◽

Jonathan Hyett ◽

Fabricio da Silva Costa ◽

Guiying Nie

Keyword(s):

Early Detection ◽

Early Onset ◽

Late Onset ◽

Pdz Domain ◽

First Trimester ◽

Potential Utility ◽

Third Trimester ◽

The Third ◽

Early Onset Preeclampsia ◽

Singleton Pregnancies

Preeclampsia is a serious disorder of human pregnancy occurring after 20 weeks of gestation. It can be divided into subtypes of early onset (<34 weeks of gestation) and late onset (>34 weeks). Presymptomatic detection to identify those at high risk is important for managing this disease. HtrA3, a serine protease with high expression in the developing placenta, exists in long (HtrA3-L) and short (HtrA3-S) isoforms. They are identical, except HtrA3-S lacks the C-terminal PDZ domain. We have previously shown by Western blot analysis that serum HtrA3 levels at the end of the first trimester are significantly higher in women who later develop preeclampsia than in controls. In this study, using highly specific HtrA3 monoclonal antibodies, we established and fully validated two enzyme-linked immunosorbent assays to detect both HtrA3 isoforms together (HtrA3-T) and HtrA3-L alone in the human serum. We then determined serum HtrA3 at 11 to 13 weeks of gestation in a cohort of singleton pregnancies that proceeded without complications or developed preeclampsia in the third trimester. Compared with controls, those who developed late-onset preeclampsia had significantly higher levels of HtrA3-L, whereas those who developed early-onset preeclampsia had significantly lower ratios of HtrA3-L/HtrA3-T. These data support a potential utility of these HtrA3 ELISAs for early detection of preeclampsia.

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Cost-effectiveness of first trimester non-invasive fetalRHDscreening for targeted antenatal anti-D prophylaxis in RhD-negative pregnant women: a model-based analysis

BJOG An International Journal of Obstetrics & Gynaecology ◽

10.1111/1471-0528.13801 ◽

2015 ◽

Vol 123 (8) ◽

pp. 1337-1346 ◽

Cited By ~ 14

Author(s):

M Neovius ◽

E Tiblad ◽

M Westgren ◽

M Kublickas ◽

K Neovius ◽

...

Keyword(s):

Cost Effectiveness ◽

Pregnant Women ◽

First Trimester ◽

Non Invasive ◽

Model Based ◽

Model Based Analysis

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Circulating circRNA as biomarkers for dilated cardiomyopathy etiology

Journal of Molecular Medicine ◽

10.1007/s00109-021-02119-6 ◽

2021 ◽

Author(s):

Marina C. Costa ◽

Maria Calderon-Dominguez ◽

Alipio Mangas ◽

Oscar Campuzano ◽

Georgia Sarquella-Brugada ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Circular Rna ◽

Circular Rnas ◽

List Type ◽

Rt Pcr ◽

Multicentric Study ◽

Non Invasive ◽

The Third ◽

Diagnostic Potential ◽

Echocardiographic Parameters

Abstract Dilated cardiomyopathy (DCM) is the third most common cause of heart failure. The multidisciplinary nature of testing — involving genetics, imaging, or cardiovascular techniques — makes its diagnosis challenging. Novel and reliable biomarkers are needed for early identification and tailored personalized management. Peripheral circular RNAs (circRNAs), a leading research topic, remain mostly unexplored in DCM. We aimed to assess whether peripheral circRNAs are expressed differentially among etiology-based DCM. The study was based on a case–control multicentric study. We enrolled 130 subjects: healthy controls (n = 20), idiopathic DCM (n = 30), ischemic DCM (n = 20), and familial DCM patients which included pathogen variants of (i) LMNA gene (n = 30) and (ii) BCL2-associated athanogene 3 (BAG3) gene (n = 30). Differentially expressed circRNAs were analyzed in plasma samples by quantitative RT-PCR and correlated to relevant systolic and diastolic parameters. The pathophysiological implications were explored through bioinformatics tools. Four circRNAs were overexpressed compared to controls: hsa_circ_0003258, hsa_circ_0051238, and hsa_circ_0051239 in LMNA-related DCM and hsa_circ_0089762 in the ischemic DCM cohort. The obtained areas under the curve confirm the discriminative capacity of circRNAs. The circRNAs correlated with some diastolic and systolic echocardiographic parameters with notable diagnostic potential in DCM. Circulating circRNAs may be helpful for the etiology-based diagnosis of DCM as a non-invasive biomarker. Key messages The limitations of cardiac diagnostic imaging and the absence of a robust biomarker reveal the need for a diagnostic tool for dilated cardiomyopathy (DCM). The circular RNA (circRNA) expression pattern is paramount for categorizing the DCM etiologies. Our peripheral circRNAs fingerprint discriminates between various among etiology-based DCM and correlates with some echocardiographic parameters. We provide a potential non-invasive biomarker for the etiology-based diagnosis of LMNA-related DCM and ischemic DCM.

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Diagnostic Performance of First Trimester Screening of Preeclampsia Based on Uterine Artery Pulsatility Index and Maternal Risk Factors in Routine Clinical Use

Diagnostics ◽

10.3390/diagnostics10040182 ◽

2020 ◽

Vol 10 (4) ◽

pp. 182

Author(s):

Max Mönckeberg ◽

Valentina Arias ◽

Rosario Fuenzalida ◽

Santiago Álvarez ◽

Victoria Toro ◽

...

Keyword(s):

High Risk ◽

Early Onset ◽

Diagnostic Performance ◽

Uterine Artery ◽

Late Onset ◽

First Trimester ◽

Maternal Risk ◽

Predictive Algorithm ◽

First Trimester Of Pregnancy ◽

Early Onset Preeclampsia

Preeclampsia is a pregnancy-specific disorder defined by new onset of hypertension and proteinuria after 20 weeks of gestation. The early detection of patients at risk of developing preeclampsia is crucial, however, predictive models are still controversial. We aim to evaluate the diagnostic performance of a predictive algorithm in the first trimester of pregnancy, in order to identify patients that will subsequently develop preeclampsia, and to study the effect of aspirin on reducing the rate of this complication in patients classified as high risk by this algorithm. A retrospective cohort including 1132 patients attending prenatal care at Clínica Dávila in Santiago, Chile, was conceived. The risk of developing preeclampsia (early and late onset) was calculated using algorithms previously described by Plasencia et al. Patients classified as high risk, in the first trimester of pregnancy, by these algorithms, were candidates to receive 100 mg/daily aspirin as prophylaxis at the discretion of the attending physician. The overall incidence of preeclampsia in this cohort was 3.5% (40/1132), and the model for early onset preeclampsia prediction detected 33% of patients with early onset preeclampsia. Among the 105 patients considered at high risk of developing preeclampsia, 56 received aspirin and 49 patients did not. Among those who received aspirin, 12% (7/56) developed preeclampsia, which is equal to the rate of preeclampsia (12% (6/49)) of those who did not receive this medication. Therefore, the diagnostic performance of an algorithm combining uterine artery Doppler and maternal factors in the first trimester predicted only one third of patients that developed preeclampsia. Among those considered at high risk for developing the disease using this algorithm, aspirin did not change the incidence of preeclampsia, however, this could be due either to the small study sample size or the type of the study, a retrospective, non-interventional cohort study.

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Association between HLA-A gene polymorphism and early-onset preeclampsia in Chinese pregnant women early-onset

BMC Pregnancy and Childbirth ◽

10.1186/s12884-020-03340-w ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Yuanyuan Zheng ◽

Cui Ma ◽

Xiaowei Liu ◽

Shaowen Wu ◽

Weiyuan Zhang ◽

...

Keyword(s):

Pregnant Women ◽

Early Onset ◽

Venous Blood ◽

Susceptibility Gene ◽

Control Group ◽

Sequencing Platform ◽

Significant Difference ◽

The Difference ◽

Early Onset Preeclampsia ◽

Idiopathic Disease

Abstract Background Preeclampsia is an idiopathic disease during pregnancy. This study explores the correlation between HLA-A polymorphism and the onset of preeclampsia. Methods The Illumina HiSeq2500 sequencing platform was used to genotyping HLA-A allele in venous blood DNA of 50 preeclampsia pregnant women and 48 normal pregnant women and umbilical cord blood DNA of their children of Han nationality in China. The frequencies and distributions of alleles and genotypes among the mothers and their children were compared between the two groups. The differences of frequencies and distributions of genotypes were compared between the two groups according to the mothers’ genotype compatibility. Results Twenty HLA-A alleles were detected in preeclampsia pregnant women and normal pregnant women; 21 HLA-A alleles were found in preeclampsia group fetuses and 22 HLA-A alleles in control group fetuses. There was no statistical difference in the HLA-A genes’ frequency between the two groups of pregnant women and their fetuses. When the sharing antigen was 1, the number of maternal-fetal pairs in the preeclampsia group was more than that in the control group; the difference was statistically significant (P < 0.05). The frequency of neither mother nor fetus carrying the HLA-A * 24: 02 gene in the preeclampsia group was significantly lower than that in the control group (P < 0.05). HLA-A gene homozygosity in fetuses of early-onset preeclampsia group was substantially higher than that of the control group (P = 0.0148); there is no significant difference in pregnant women’s genes homozygosity between early-onset preeclampsia group and the control group. Conclusions HLA-A * 24: 02 may be a susceptibility gene for early preeclampsia.

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Zika Virus Infection in a Cohort of Pregnant Women with Exanthematic Disease in Manaus, Brazilian Amazon

Viruses ◽

10.3390/v12121362 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1362

Author(s):

Elijane de Fátima Redivo ◽

Camila Bôtto Menezes ◽

Márcia da Costa Castilho ◽

Marianna Brock ◽

Evela da Silva Magno ◽

...

Keyword(s):

Virus Infection ◽

Pregnant Women ◽

Zika Virus ◽

Descriptive Analysis ◽

First Trimester ◽

Adverse Outcomes ◽

Rt Pcr ◽

Zika Virus Infection ◽

Adverse Pregnancy ◽

In Pregnancy

The epidemic transmission of Zika virus (ZIKV) in Brazil has been identified as a cause of microcephaly and other neurological malformations in the babies of ZIKV-infected women. The frequency of adverse outcomes of Zika virus infection (ZIKVi) in pregnancy differs depending on the characteristics of exposure to infection, the time of recruitment of research participants, and the outcomes to be observed. This study provides a descriptive analysis—from the onset of symptoms to delivery—of a cohort registered as having maternal ZIKVi in pregnancy, from November 2015 to December 2016. Suspected cases were registered at a referral center for infectious and tropical diseases in Manaus, in the Amazonian region of Brazil. Of 834 women notified, 762 women with confirmed pregnancies were enrolled. Reverse-transcriptase polymerase chain reaction (RT-PCR) confirmed ZIKVi in 42.3% of the cohort. In 35.2% of the cohort, ZIKV was the sole infection identified. Severe adverse pregnancy outcomes (miscarriage, stillbirth, or microcephaly) were observed in both RT-PCR ZIKV-positive (5.0%) and ZIKV-negative (1.8%) cases (RR 3.1; 95% IC 1.4–7.3; p < 0.05), especially during the first trimester of pregnancy (RR 6.2, 95% IC 2.3–16.5; p < 0.001). Although other infectious rash diseases were observed in the pregnant women in the study, having confirmed maternal ZIKVi was the most important risk factor for serious adverse pregnancy events.

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