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Journal of Reproductive Immunology May 2024Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and are important for placenta formation during early pregnancy. Recurrent pregnancy loss (RPL) is...
Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and are important for placenta formation during early pregnancy. Recurrent pregnancy loss (RPL) is associated with abnormalities in endometrial extracellular matrix remodeling. This study aimed to elucidate the roles of MMP2 and MMP9 in RPL pathogenesis. In total, 295 women with a history of RPL and 101 controls were included in this genetic study. Genotype analysis was performed using polymerase chain reaction (PCR) restriction fragment length polymorphisms. For proteolytic analysis, decidua and villi were collected from 10 RPL-miscarried women with normal fetal chromosomes (NC) and 19 women with fetal chromosome aberrations (AC). The expression of MMP2 and MMP9 in the decidua and villi was measured by IHC and ELISA. All samples were collected after obtaining informed consent. There were no statistically significant differences in MMP2-735 C/T and MMP9-1562 C/T frequencies between women with RPL and the controls. There was no significant difference in MMP2 expression levels in the villi; however, MMP9 expression was significantly higher in normal fetal chromosomes. In the decidua, the expression of MMP2 in the NC group was significantly lower, and MMP9 in the NC group was significantly higher than in the AC group. Although no differences in MMP2-735 C/T and MMP9-1562 C/T gene polymorphisms were observed in the present study, it is suggested that differences at the protein level are involved in the pathogenesis of RPL since MMP expression is not only regulated by genes but also by local inflammation and various inductive signals.
PubMed: 38878627
DOI: 10.1016/j.jri.2024.104270 -
Extracellular Vesicle Jun 2024Pregnant women and their fetuses are often excluded from clinical trials due to missing drug-related pre-clinical trial information at the human feto-maternal interface...
Pregnant women and their fetuses are often excluded from clinical trials due to missing drug-related pre-clinical trial information at the human feto-maternal interface (FMi). The two interfaces-placenta/decidua and fetal membranes/decidua are gatekeepers of drug transport; however, testing their functions is impractical during pregnancy. Limitations of current / models have hampered drug development and testing during pregnancy. Hence, major complications like preterm births and maternal and neonatal mortalities remain high. Advancements in organ-on-chip (OOC) platforms to test drug kinetics and efficacy and novel extracellular vesicle-based fetal drug delivery are expected to accelerate preclinical trials related to pregnancy complications. Here we report the development and testing of a humanized multi-organ fetal membrane/placenta (fetal)-decidua (maternal) interface OOC (FMi-PLA-OOC) that contains seven cell types interconnected through microchannels to maintain intercellular interactions as seen . Cytotoxicity, propagation, mechanism of action, and efficacy of engineered extracellular vesicles containing anti-inflammatory interleukin (IL)-10 (eIL-10) were evaluated to reduce FMi inflammation associated with preterm birth. A healthy and disease model (lipopolysaccharide-infectious inflammation) of the FMi-PLA-OOC was created and co-treated with eIL-10. eIL-10 propagated from the maternal to fetal side within 72-hours, localized in all cell types, showed no cytotoxicity, activated IL-10 signaling pathways, and reduced lipopolysaccharide-induced inflammation (minimized NF-kB activation and proinflammatory cytokine production). These data recapitulated eIL-10s' ability to reduce inflammation and delay infection-associated preterm birth in mouse models, suggesting FMi-PLA-OOC as an alternative approach to using animal models. Additionally, we report the utility of eIL-10 that can traverse through FMis to reduce inflammation-associated pregnancy complications.
PubMed: 38872854
DOI: 10.1016/j.vesic.2024.100035 -
Placenta Jun 2024Factors contributing to recurrent pregnancy loss (RPL) in more than half of the cases are still unknown. The incidence and societal impact of this condition requires...
INTRODUCTION
Factors contributing to recurrent pregnancy loss (RPL) in more than half of the cases are still unknown. The incidence and societal impact of this condition requires urgent elucidation of the mechanisms behind it, which could aid in significant improvement of clinical management.
MATERIALS AND METHODS
Using a highly efficient in-solution digestion method and label-free data-independent LC-MS/MS acquisition with ion mobility, we performed comparative proteomics analysis of the decidua tissues from 19 RPL patients and 10 controls. Differentially abundant proteins (DAPs) were compared and correlated with 3 publicly available transcriptomic datasets and the expression of selected biomarkers was tested by qPCR in decidua and chorionic villi from an extended cohort.
RESULTS
From 1952 proteins identified based on ≥2 peptides, the statistically significant difference in abundance (Anova p ≤ 0.05) and fold change ≥1.2 showed 85 proteins. Pathway analysis using Reactome, KEGG and Wiki pathways identified enrichment of "Signaling by ROBO receptors", "RNA degradation" and "Cytoplasmic Ribosomal Proteins". The correlation between protein and gene expression in decidua revealed that the down-regulated ribosomal proteins in our dataset (RPS15, RPS17, RPL27A, RPL35A and RPL18) showed the same regulation trend at the mRNA level, which was later confirmed for transcripts of RPS15 and RPL18 in our cohort.
DISCUSSION
Our data suggests that the potential causes of RPL from the maternal side could be associated with impaired RNA processing machinery. Furthermore, the list of DAPs in RPL opens future investigations in terms of screening novel gene variants predisposing to pregnancy failure and developing biomarkers for RPL risk.
PubMed: 38870839
DOI: 10.1016/j.placenta.2024.06.005 -
Redox Biology Aug 2024Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and...
Manganese porphyrin-based treatment improves fetal-placental development and protects against oxidative damage and NLRP3 inflammasome activation in a rat maternal hypothyroidism model.
Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP] (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1β, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, Gpx1, GRP78, and Chop to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, Nlrp3, and Caspase1 in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface.
Topics: Animals; Pregnancy; Female; Rats; Hypothyroidism; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Inflammasomes; Disease Models, Animal; Placenta; Placentation; Antioxidants; Endoplasmic Reticulum Stress; Fetal Development; Manganese; Metalloporphyrins; Endoplasmic Reticulum Chaperone BiP
PubMed: 38870780
DOI: 10.1016/j.redox.2024.103238 -
Proceedings of the National Academy of... Jun 2024The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and...
The process of human parturition involves inflammation at the interface where fetal chorion trophoblast cells interact with maternal decidual stromal (DS) cells and maternal immune cells in the decidua (endometrium of pregnancy). This study tested the hypothesis that inflammation at the chorion-decidua interface (CDI) induces labor by negating the capacity for progesterone (P4) to block labor and that this is mediated by inactivation of P4 in DS cells by aldo-keto reductase family 1 member C1 (AKR1C1). In human, Rhesus macaque, and mouse CDI, expression increased in association with term and preterm labor. In a human DS cell line and in explant cultures of term human fetal membranes containing the CDI, the prolabor inflammatory cytokine, interleukin-1ß (IL-1ß), and media conditioned by LPS-stimulated macrophages increased expression and coordinately reduced nuclear P4 levels and P4 responsiveness. Loss of P4 responsiveness was overcome by inhibition of AKR1C1 activity, inhibition of expression, and bypassing AKR1C1 activity with a P4 analog that is not metabolized by AKR1C1. Increased P4 activity in response to AKR1C1 inhibition was prevented by the P4 receptor antagonist RU486. Pharmacologic inhibition of AKR1C1 activity prevented parturition in a mouse model of inflammation-induced preterm parturition. The data suggest that inflammatory stimuli at the CDI drive labor by inducing AKR1C1-mediated P4 inactivation in DS cells and that inhibiting and/or bypassing of AKR1C1-mediated P4 inactivation is a plausible therapeutic strategy to mitigate the risk of inflammation-associated preterm birth.
Topics: Female; Animals; Progesterone; Decidua; Humans; Mice; Stromal Cells; Parturition; Pregnancy; Inflammation; Macaca mulatta; 20-Hydroxysteroid Dehydrogenases; Interleukin-1beta; Chorion
PubMed: 38861608
DOI: 10.1073/pnas.2400601121 -
Open Medicine (Warsaw, Poland) 2024With unknown etiology and limited treatment options, unexplained recurrent pregnancy loss (URPL) remains a thorny problem. Ferroptosis, a newly identified type of cell...
AIM
With unknown etiology and limited treatment options, unexplained recurrent pregnancy loss (URPL) remains a thorny problem. Ferroptosis, a newly identified type of cell death, has been shown to be crucial in the development in reproductive disorders. This study aims to explore the specific mechanism of ferroptosis in URPL and to uncover whether alpha-lipoic acid (ALA) can inhibit ferroptosis, and then exert a protective effect in URPL.
METHOD
The decidua tissues of URPL and control patients who actively terminated pregnancy were collected. The CBA/J × DBA/2 murine models of URPL were established, and were randomly treated with peroxisome proliferator activated receptor γ (PPARγ) agonists (Rosiglitazone) and ALA. The CBA/J × BALB/c murine models of normal pregnancy were intraperitoneally injected with PPARγ inhibitors (T0070907). Here, we used reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH)/GSSG, and FeRhoNox-1 analysis to detect the level of ferroptosis. We used quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis to evaluate the mRNA level of PPARγ. Besides, western blot and immunofluorescence were utilized to test the expression profile of PPARγ/nuclear factor erythroid 2-related factor 2 (NRF2)/glutathione peroxidase 4 (GPX4).
RESULTS
In this study, we found that iron deposition was increased in the decidual tissue of patients with URPL. Additionally, the changes in cell morphology, the level of ROS, MDA, GSH, and the expression of ferroptosis marker proteins NRF2/GPX4 confirmed activated ferroptosis in URPL. Besides, bioinformatics analysis combined with experiments confirmed that PPARγ was critical in triggering NRF2/GPX4 pathway in URPL. Furthermore, URPL mouse models were established, and the results showed that PPARγ/NRF2/GPX4-mediated ferroptosis was also significantly increased, which could be mitigated by ALA treatment.
CONCLUSION
Overall, these findings suggest that ferroptosis may play an important role in URPL, and ALA might be a promising therapeutic drug for improving pregnancy outcomes in URPL via targeting the PPARγ/NRF2/GPX4 pathway.
PubMed: 38859880
DOI: 10.1515/med-2024-0963 -
Biomedical Optics Express May 2024In histopathology, it is highly crucial to have chemical and structural information about tissues. Additionally, the segmentation of zones within a tissue plays a vital...
In histopathology, it is highly crucial to have chemical and structural information about tissues. Additionally, the segmentation of zones within a tissue plays a vital role in investigating the functions of these regions for better diagnosis and treatment. The placenta plays a vital role in embryonic and fetal development and in diagnosing some diseases associated with its dysfunction. This study provides a label-free approach to obtain the images of mature mouse placenta together with the chemical differences between the tissue compartments using Raman spectroscopy. To generate the Raman images, spectra of placental tissue were collected using a custom-built optical setup. The pre-processed spectra were analyzed using statistical and machine learning methods to acquire the Raman maps. We found that the placental regions called decidua and the labyrinth zone are biochemically distinct from the junctional zone. A histologist performed a comparison and evaluation of the Raman map with histological images of the placental tissue, and they were found to agree. The results of this study show that Raman spectroscopy offers the possibility of label-free monitoring of the placental tissue from mature mice while simultaneously revealing crucial structural information about the zones.
PubMed: 38855670
DOI: 10.1364/BOE.521500 -
Annual Review of Virology Jun 2024Interferon lambda (IFN-λ, type III IFN, IL-28/29) is a family of antiviral cytokines that are especially important at barrier sites, including the maternal-fetal... (Review)
Review
Interferon lambda (IFN-λ, type III IFN, IL-28/29) is a family of antiviral cytokines that are especially important at barrier sites, including the maternal-fetal interface. Recent discoveries have identified important roles for IFN-λ during pregnancy, particularly in the context of congenital infections. Here, we provide a comprehensive review of the activity of IFN-λ at the maternal-fetal interface, highlighting cell types that produce and respond to IFN-λ in the placenta, decidua, and endometrium. Further, we discuss the role of IFN-λ during infections with congenital pathogens including Zika virus, human cytomegalovirus, rubella virus, and . We discuss advances in experimental models that can be used to fill important knowledge gaps about IFN-λ-mediated immunity.
PubMed: 38848605
DOI: 10.1146/annurev-virology-111821-101531 -
Frontiers in Endocrinology 2024Leptin and its receptors are expressed by the human placenta throughout gestation, yet the role of leptin in early human placental development is not well characterized....
INTRODUCTION
Leptin and its receptors are expressed by the human placenta throughout gestation, yet the role of leptin in early human placental development is not well characterized. Leptin is overexpressed in the placentas from preeclamptic (PE) pregnancies. PE can result from the impaired invasion of fetal placental cells, cytotrophoblasts (CTBs), into the maternal decidua. We hypothesized that elevated leptin levels would impair human CTB invasion.
METHODS
The effects of leptin on the invasion of human CTBs were evaluated in three cell models, HTR-8/SVneo cells, primary CTBs, and placental villous explants using invasion assays. Further, leptin receptor expression was characterized in all three cell models using RT-PCR. Further phosphokinase assays were performed in HTR-8/SVneo cells to determine signaling pathways involved in CTB invasion in response to differential leptin doses.
RESULTS
We found that, prior to 8 weeks gestation, leptin promoted CTB invasion in the explant model. After 11 weeks gestation in explants, primary CTBs and in HTR-8/SVneo cells, leptin promoted invasion at moderate but not at high concentrations. Further, leptin receptor characterization revealed that leptin receptor expression did not vary over gestation, however, STAT, PI3K and MAPK pathways showed different signaling in response to varied leptin doses.
DISCUSSION
These data suggest that the excess placental leptin observed in PE may cause impaired CTB invasion as a second-trimester defect. Leptin's differential effect on trophoblast invasion may explain the role of hyperleptinemia in preeclampsia pathogenesis.
Topics: Humans; Trophoblasts; Leptin; Female; Pregnancy; Gestational Age; Receptors, Leptin; Placenta; Pre-Eclampsia; Dose-Response Relationship, Drug; Signal Transduction; Placentation; Cell Movement
PubMed: 38846494
DOI: 10.3389/fendo.2024.1386309 -
Planta Medica Jun 2024The global increase in the incidence of wounds is concerning and fuels the search for new treatment options. The use of traditional medicinal plants in wound healing... (Review)
Review
The global increase in the incidence of wounds is concerning and fuels the search for new treatment options. The use of traditional medicinal plants in wound healing represents an appreciated available therapeutic possibility. This work introduces the VOLKSMED database, which contains plants and other materials used in Austrian folk medicine, either as monographs or mixtures. This work focuses on the monographs of the database. Concerning wound healing, sp., sp., and sp. are the most commonly used plants. The focus of this paper is set on selected lesser-known plants ( sp., sp., sp., ) and their status quo in literature concerning wound healing. A systematic search using the databases SciFinder, SCOPUS, and PubMed yielded substantial evidence for the wound healing potential of sp., sp., the Pinaceae and , as well as and clinical studies substantiate their use in Austrian folk medicine. According to the literature, especially and would be worth investigating in-depth since data concerning their wound healing effects - even though scarce - are convincing. In conclusion, the VOLKSMED database contains promising opportunities for further treatment options in the field of wound healing. Future research should consider the listed plants to support their traditional use in Austrian folk medicine and possibly promote the implementation of old knowledge in modern medicine.
Topics: Austria; Wound Healing; Medicine, Traditional; Humans; Plants, Medicinal; Phytotherapy; Databases, Factual; Plant Extracts
PubMed: 38843790
DOI: 10.1055/a-2225-7545