Introduction: Placental inflammation is implicated in the pathophysiology of many pregnancy complications, including fetal growth restriction, preeclampsia, gestational diabetes, and choriocarcinoma. Mitochondrial dysfunction, one of the outcomes of placental inflammation, is characterized by loss of membrane potential, accumulation of oxygen radicals, mitochondrial protein folding defects, and disturbances in mitochondrial dynamics. Protein kinase R (PKR) is stimulated by double-stranded RNA and bacterial endotoxins in the presence of pathogens and is a critical immune response enzyme. PKR is also correlated with the cell death response during endoplasmic reticulum stress. In this study, we aim to investigate the effects of PKR activity stimulated by lipopolysaccharide (LPS), and double-stranded RNA analog (Poly I:C) on mitochondrial unfolded protein response (mtUPR), mitochondrial membrane potential, apoptosis, and oxidative stress in placental trophoblasts.
Methods: We applied LPS and Poly I:C to BeWo cells to induce PKR activation. In addition, cells were treated with 2-aminopurine (2-AP) to inhibit the kinase activity of PKR. Protein levels of ATP-dependent Clp protease proteolytic subunit (CLPP) and heat shock protein 60 (HSP60) were determined after treatments. Apoptotic markers were detected by real-time PCR and flow cytometry. PKR-induced reactive oxygen radicals (ROS) accumulation and mitochondrial membrane potential change were assessed by flow cytometry.
Results: It was determined that PKR activation-induced apoptosis in BeWo cells by reducing the levels of mtUPR proteins (CLPP and HSP60) and caused a decrease in mitochondrial membrane potential. PKR inhibition was sufficient for decreases in apoptotic markers and caused a reduction in the ratio of depolarized and ROS (+) cells.
Discussion: Our results showed that LPS and Poly I:C administration stimulated PKR in BeWo cells in vitro. Furthermore, PKR activation is correlated with the levels of proteins involved in mitochondrial homeostasis and apoptosis. Our findings will contribute to understanding the role of PKR activation in placental inflammation and related diseases.
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http://dx.doi.org/10.1016/j.placenta.2023.07.007 | DOI Listing |
Placenta
December 2024
Johns Hopkins University Bloomberg School of Public Health, USA. Electronic address:
Chronic arsenic exposure affects over 140 million people globally. While arsenic easily crosses the placenta, the specific mechanisms impacting placental immune cell populations and fetal health are unclear. Maternal arsenic exposure is epidemiologically linked to increased infection risk, mortality, and cancer susceptibility in offspring, emphasizing the importance of understanding placentally-mediated immune effects.
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January 2025
Department of Obstetrics, Gynecology and Reproductive Health, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.
At the maternal-fetal interface, tightly regulated levels of retinoic acid (RA), the physiologically active metabolite of vitamin A, are required for embryo implantation and pregnancy success. Herein, we utilize mouse models, primary human cells, and pharmacological tools to demonstrate how depletion of RA signaling via RA receptor (RAR) disrupts implantation and progression of early pregnancy. To inhibit RAR signaling during early pregnancy, BMS493, an inverse pan-RAR agonist that prevents RA-induced differentiation, was administered to pregnant mice during the peri-implantation period.
View Article and Find Full Text PDFAm J Reprod Immunol
January 2025
Department of Environmental Immunology, Helmholtz Centre for Environmental Research, Leipzig, Saxony, Germany.
Problem: Although it is still uncertain whether Severe Acute Respiratory Coronavirus (SARS-CoV-2) placental infection and vertical transmission occur, inflammation during early pregnancy can have devastating consequences for gestation itself and the growing fetus. If and how SARS-CoV-2-specific immune cells negatively affect placenta functionality is still unknown.
Method Of Study: We stimulated peripheral blood mononuclear cells (PBMCs) from women of reproductive age with SARS-CoV-2 peptides and cocultured them with trophoblast spheroids (HTR-8/SVneo and JEG-3) to dissect if SARS-CoV-2-activated immune cells can interfere with trophoblast functionality.
Cell Biosci
January 2025
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA.
Spontaneous preterm birth (sPTB) poses significant challenges, affecting neonatal health and neurodevelopmental outcomes worldwide. The specific effects of placental trophoblasts on the pathological development of sPTB subtypes-preterm premature rupture of fetal membranes (pPROM) and spontaneous preterm labor (sPTL)-are not fully understood, making it crucial to uncover these impacts for the development of effective therapeutic strategies. Using single-nucleus RNA sequencing, we investigated transcriptomic and cellular differences at the maternal-fetal interface in pPROM and sPTL placentas.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Laboratory of Comparative Developmental Physiology, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 119334 Moscow, Russia.
Available evidence from animal studies suggests that placental serotonin plays an important role in proper fetal development and programming by altering brain circuit formation, which later translates into altered abnormal adult behaviors. Several environmental stimuli, including stress and maternal inflammation, affect placental and, hence, fetal serotonin levels and thus may disturb fetal brain development. We investigated the effect of prenatal stress of varying intensities on the formation of adaptive behaviors in mouse offspring and the role of placental serotonin in these processes.
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