CYP1A1, GSTT1, IL-6 and IL-8 transcription and IL-6 secretion on umbilical endothelial cells from hypertensive pregnant women: Preliminary results

Reyes-Aguilar, Sandra S.; Poblete-Naredo, Irais; Rodríguez-Yáñez, Yury; Corona-Núñez, Rogelio O.; Ortiz-Robles, Christian D.; Calderón-Aranda, Emma S.; Albores, Arnulfo

doi:10.1016/j.preghy.2019.09.002

Cited by 4 publications

(5 citation statements)

References 19 publications

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“…Our results regarding the differences in IL-8 and LAM between CTR and EO-PE fpECAs on transcriptional and protein levels are in contrast to the data from other studies [ 32 , 33 ]. In those studies, the authors computed the differences between HUVEC isolated from healthy and PE placentas.…”

Section: Discussioncontrasting

confidence: 99%

The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas

Schröder‐Heurich

Mercnik

et al. 2023

IJMS

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Hydroxychloroquine (HCQ), an anti-malarial drug, is suggested as a promising candidate for the treatment of pregnancy-related disorders associated with endothelial activation, among which there is preeclampsia (PE). Arterial feto-placental endothelial cells (fpECAs) were isolated from control (CTR) and early-onset preeclamptic (EO-PE) placentas. The aim of this study was to test potential protective effects of HCQ in an in vitro model of endothelial activation as well as in cells isolated from EO-PE placentas. To mimic PE conditions, CTR fpECAs were exposed to a pro-inflammatory environment consisting of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1β (furtherly referred as MIX) with or without varying concentrations of HCQ (1 µg/mL and 10 µg/mL). Their effect on wound healing and endothelial barrier integrity was analyzed. Variations in the expression of IL-8 and leukocyte adhesion molecules (LAM) on both mRNA and protein levels were determined between CTR and PE fpECAs in the presence or absence of HCQ. MIX decreased wound healing and stability of the endothelial barrier, but HCQ did not affect it. Significant differences between CTR and EO-PE fpECAs were observed in IL-8 mRNA, protein secretion, and vascular cell adhesion protein 1 (VCAM-1) mRNA expression levels. After challenging CTR fpECAs with MIX, upregulation of both mRNA and protein levels was observed in all molecules. Combined treatment of HCQ and MIX slightly lowered VCAM-1 total protein amount. In CTR fpECAs, treatment with low concentrations of HCQ alone (1 µg/mL) reduced basal levels of IL-8 and VCAM-1 mRNA and secretion of IL-8, while in EO-PE fpECAs, a higher (10µg/mL) HCQ concentration slightly reduced the gene expression of IL-8. Conclusion: These results provide additional support for the safety of HCQ, as it did not adversely affect endothelial functionality in control fpECAs at the tested concentration. Furthermore, the observed limited effects on IL-8 secretion in EO-PE fpECAs warrant further investigation, highlighting the need for clinical trials to assess the potential therapeutic effects of HCQ in preeclampsia. Conducting clinical trials would offer a more comprehensive understanding of HCQ’s efficacy and safety, allowing us to explore its potential benefits and limitations in a real-world clinical setting.

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Section: Discussioncontrasting

confidence: 99%

The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas

Schröder‐Heurich

Mercnik

et al. 2023

IJMS

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“…No prior research studies were identified that reported links between the remaining DMRs in trimester 3 or in trimester 2 when we conducted PubMed searches within the context of pregnancy (keywords: gene name AND pregnancy) and PE (keywords: gene name AND preeclampsia). Of the three DMRs identified in trimester 1, CYP1A1 has previously been linked to pregnancy [29][30][31]. CYP1A1 protein is involved in the synthesis of cholesterol, steroids, and lipids, as well as in drug metabolism; elevated CYP1A1 protein levels have been previously associated with premature birth, intrauterine growth restriction, and placental abruption, but not PE [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…Of the three DMRs identified in trimester 1, CYP1A1 has previously been linked to pregnancy [29][30][31]. CYP1A1 protein is involved in the synthesis of cholesterol, steroids, and lipids, as well as in drug metabolism; elevated CYP1A1 protein levels have been previously associated with premature birth, intrauterine growth restriction, and placental abruption, but not PE [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy

Liu

Ray

et al. 2023

Epigenetics Commun.

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Background While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study’s purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls). Results In the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases, n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample. Conclusions The discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1–2 and significant DMRs that were not examined in the replication phase.

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“…Valencia-Ortega et al [ 65 ] reported higher umbilical serum concentrations of IL-6 and TNF- α in PE than in the control group. Reyes-Aguilar et al [ 66 ], studying the transcription of proinflammatory cytokine genes in umbilical cord blood, identified lower levels of IL-6 transcripts in PE women than in normotensive women. Thus, the authors suggested that the decrease in the release of inflammatory cytokines by umbilical vein endothelial cells in women with PE is an attempt to protect the foetus.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the authors suggested that the decrease in the release of inflammatory cytokines by umbilical vein endothelial cells in women with PE is an attempt to protect the foetus. This is clinically significant because neonates of mothers with PE have reduced immune activity, a fact supported by their augmented susceptibility to infections [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Biomarkers of Inflammation and Redox Imbalance in Umbilical Cord in Pregnancies with and without Preeclampsia and Consequent Perinatal Outcomes

Fragoso

Ferreira

Tenório

et al. 2021

Oxidative Medicine and Cellular Longevity

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Objective. To compare redox imbalance and inflammation biomarkers in umbilical cords from pregnancies with and without preeclampsia (PE) and to analyse their relationships with perinatal outcomes. Methods. A controlled cross-sectional study was conducted in Maceió, Alagoas, Brazil, that involved pregnant women with PE and a group of women without the disease, through the application of a standardized questionnaire. After delivery, umbilical cord samples were collected to measure antioxidant defense, products from oxidative damage, and inflammation biomarkers such as myeloperoxidase (MPO), interleukin- (IL-) 6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α). Statistical analyses were performed using Stata version 13.0 software and IBM Statistical Package for the Social Sciences (SPSS) 20.0, adopting a 95% confidence level ( α = 0.05 ), with the chi-square test, the Wilcoxon–Mann–Whitney test, and the multinomial and Poisson regression tests. Results. One hundred PE pregnant women and 50 women without the disease were studied. The umbilical cords from PE pregnancies showed higher levels of reduced glutathione (GSH) ( p ≤ 0.001 ), glutathione peroxidase (GPx) ( p = 0.016 ), and malondialdehyde (MDA) ( p = 0.028 ) and lower levels of IL-6 ( p = 0.030 ) and TNF-α ( p ≤ 0.001 ) than the other group, with some associations among these biomarkers with perinatal outcomes. Conclusion. The higher levels of GSH and GPx, in addition to the lower levels of IL-6 and TNF-α, found in the PE umbilical cord, may result from adaptive mechanisms to maintain the oxidative and inflammatory balance; however, despite these changes, the damage to the cell membranes was not minimized, as the MDA level was higher in women with PE than in women without the disease. This implies that a redox imbalance is present, confirming that other physiological and adaptive mechanisms are being activated to preserve foetal health. Therefore, the present work unveils an important role of the umbilical cord in controlling redox imbalance and inflammation in PE pregnancies. Our results reinforce the necessity for continuous research on GSH as a protective compound for the perinatal outcome, especially in PE women.

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CYP1A1, GSTT1, IL-6 and IL-8 transcription and IL-6 secretion on umbilical endothelial cells from hypertensive pregnant women: Preliminary results

Cited by 4 publications

References 19 publications

The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas

The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas

A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy

Biomarkers of Inflammation and Redox Imbalance in Umbilical Cord in Pregnancies with and without Preeclampsia and Consequent Perinatal Outcomes

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