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Immune Dysfunction Mediated by the ceRNA Regulatory Network in Human Placenta Tissue of Intrahepatic Cholestasis Pregnancy.

ABSTRACT: Pregnancy-related intrahepatic cholestasis (ICP) is a serious complication with adverse perinatal outcomes of preterm labor, fetal distress, or stillbirth. As a result, it is important to investigate and identify the potential critical pathogenic mechanisms of ICP. First, we collected the placental tissues from the ICP with placental weight and fetal birth weight loss for the whole transcriptome sequencing. Then we analyzed the differentially expressed (DE) circRNAs (DEcircRNAs) by SRPBM, DElncRNAs by FRKM, DEmiRNAs by TPM, and DEmRNAs by TPM and RSEM. Based on differential expression of term pregnancy placental tissues from pregnancies impacted by ICP (n=7) as compared to gestational aged matched control tissues (n=5), the circ/lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory networks were constructed. The ceRNA regulatory networks covered 3,714 events, including 21 DEmiRNAs, 36 DEcircRNAs, 146 DElncRNAs, and 169 DEmRNAs. According to the functional analysis, ICP complications were linked to the immune system, signal transduction, endocrine system, cell growth and death, and transport and catabolism. Further evidence suggested that the expression of immune-related genes KLRD1, BRAF, and NFATC4 might have a potential ceRNA mechanism by individual lncRNA sponging miR372-3p, miR-371a-3p, miR-7851-3p, and miR-449a to control downstream the level of TNF-α, IFN-γ, and IL-10, thereby regulating the pathophysiology of ICP. Furthermore, our results were validated by the qRT-PCR, western blotting and ELISA assays. In conclusion, this study is the first to evaluate placental ceRNA networks in pregnancies affected by ICP, showing alterations in immune regulatory networks which may impact fetal and placental growth. Overall our these data suggest that the ceRNA regulatory network may refine biomarker predictions for developing novel therapeutic approaches in ICP.

SUBMITTER: Wang Y

PROVIDER: S-EPMC9263217 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsIntrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of stillbirth. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in patients with ICP who were or were not treated with ursodeoxycholic acid (UDCA).MethodsBile acid profiles and NT-proBNP, a marker of ventricular dysfunction, were assayed in umbilical venous serum from 15 controls and 76 ICP cases (36 untreated, 40 UDCA-treated). Fetal electrocardiogram traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability (HRV) parameters were measured in 2 behavioral states (quiet and active sleep).ResultsIn untreated ICP, fetal total serum bile acid (TSBA) concentrations (r = 0.49, p = 0.019), hydrophobicity index (r = 0.20, p = 0.039), glycocholate concentrations (r = 0.56, p = 0.007) and taurocholate concentrations (r = 0.44, p = 0.039) positively correlated with fetal NT-proBNP. Maternal TSBA (r = 0.40, p = 0.026) and alanine aminotransferase (r = 0.40, p = 0.046) also positively correlated with fetal NT-proBNP. There were no significant correlations between maternal or fetal serum bile acid concentrations and fetal HRV parameters or NT-proBNP concentrations in the UDCA-treated cohort. Fetal PR interval length positively correlated with maternal TSBA in untreated (r = 0.46, p = 0.027) and UDCA-treated ICP (r = 0.54, p = 0.026). Measures of HRV in active sleep and quiet sleep were significantly higher in untreated ICP cases than controls. HRV values in UDCA-treated cases did not differ from controls.ConclusionsElevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterized by increased NT-proBNP concentration, PR interval length and HRV. UDCA treatment partially attenuates this phenotype.Lay summaryThe risk of stillbirth in intrahepatic cholestasis of pregnancy (ICP) is linked to the level of bile acids in the mother which are thought to disrupt the baby's heart rhythm. We found that babies of women with untreated ICP have abnormally functioning hearts compared to those without ICP, and the degree of abnormality is closely linked to the level of harmful bile acids in the mother and baby's blood. Babies of women with ICP who received treatment with the drug UDCA do not have the same level of abnormality in their hearts, suggesting that UDCA could be a beneficial treatment in some ICP cases, although further clinical trials are needed to confirm this.

Project description:BackgroundIntrahepatic cholestasis of pregnancy (ICP) is likely to lead to unfavorable consequences. Total bile acid (TBA) is thought to be the sole ICP indicator available as of now, but it comes with some kind of restrictions in terms of sensitivity and specificity. We were endeavoring to find potential diagnostic biomarkers for ICP in this investigation.MethodsThis case-control study with a prospective nature included 40 females in the stage of pregnancy who were diagnosed with ICP. It also included another 20 females who were also pregnant but with sound physical condition(control). Placental and plasma samples were collected from all females that were in the stage of pregnancy, except for 20 ICP patients, in which only plasma was collected. We used four-dimensional data-independent acquisition followed by enzyme-linked immunosorbent assay and immunohistochemistry to identify and validate plasma and placental profiles in ICP patients and controls. Bioinformatics was adopted in an effort to demonstrate the relevant biological processes and signalling pathways. Correlation analysis was used to analyse the consistency of tissue and plasma protein expression and the correlation between sequencing and experimental results.ResultsThe expression levels of nectin-1 (NECTIN1), Kunitz-type protease inhibitor 1 (SPINT1), and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) were remarkably higher in ICP patients than in controls. However, heparin cofactor 2 (SERPIND1) expression levels in female participants in the stage of pregnancy who were diagnosed with ICP were remarkably lower than those pregnant females with good physical fitness. In addition to the negative correlation between SERPIND1 and TBA, NECTIN1, SPINT1, and ITIH3 expression positively correlated with TBA. Area under the receiver operating characteristic curve (AUC) values of 0.7925, 0.8313, 0.8163, and 0.9025, respectively, were used to assess the diagnostic accuracies of NECTIN1, SPINT1, ITIH3, and SERPIND1. AUC (0.9438) was considerably greater when NECTIN1, SPINT1, and SERPIND1 were integrated, according to binary logistic regression. The AUC of the ROC curve for various combinations of SERPIND1 and other indicators was higher than itself, thus providing a more reliable ICP diagnosis. Furthermore, according to the bioinformatics analysis, the NECTIN1, SPINT1, ITIH3, and SERPIND1 were identified as secreted proteins because they were localized in the extracellular region.ConclusionsThis research discovered new non-invasive ICP indicators. On top of this, it sheds new light on the crucial diagnostic function of secreted proteins in ICP.

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Immune Dysfunction Mediated by the ceRNA Regulatory Network in Human Placenta Tissue of Intrahepatic Cholestasis Pregnancy.

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