International Journal of Molecular Sciences

Editorial

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4 pages, 191 KiB

Open AccessEditorial

Pathogenesis of Pregnancy-Related Complications 1.0 and 2.0

by Ilona Hromadnikova

Int. J. Mol. Sci. 2022, 23(6), 3020; https://doi.org/10.3390/ijms23063020 - 11 Mar 2022

Cited by 1 | Viewed by 2012

Abstract

These Special Issue IJMS were dedicated to the major complications responsible for maternal and perinatal morbidity and mortality, such as gestational hypertension (GH), preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), preterm birth, and chronic venous disease [...] Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

Research

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13 pages, 2150 KiB

Open AccessArticle

Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model

by Sarah M. Kedziora, Kristin Kräker, Lajos Markó, Julia Binder, Meryam Sugulle, Martin Gauster, Dominik N. Müller, Ralf Dechend, Nadine Haase and Florian Herse

Int. J. Mol. Sci. 2021, 22(7), 3762; https://doi.org/10.3390/ijms22073762 - 5 Apr 2021

Cited by 5 | Viewed by 3405

Abstract

Preeclampsia (PE) is characterized by the onset of hypertension (≥140/90 mmHg) and presence of proteinuria (>300 mg/L/24 h urine) or other maternal organ dysfunctions. During human PE, renal injuries have been observed. Some studies suggest that women with PE diagnosis have an increased [...] Read more.

Preeclampsia (PE) is characterized by the onset of hypertension (≥140/90 mmHg) and presence of proteinuria (>300 mg/L/24 h urine) or other maternal organ dysfunctions. During human PE, renal injuries have been observed. Some studies suggest that women with PE diagnosis have an increased risk to develop renal diseases later in life. However, in human studies PE as a single cause of this development cannot be investigated. Here, we aimed to investigate the effect of PE on postpartum renal damage in an established transgenic PE rat model. Female rats harboring the human-angiotensinogen gene develop a preeclamptic phenotype after mating with male rats harboring the human-renin gene, but are normotensive before and after pregnancy. During pregnancy PE rats developed mild tubular and glomerular changes assessed by histologic analysis, increased gene expression of renal damage markers such as kidney injury marker 1 and connective-tissue growth factor, and albuminuria compared to female wild-type rats (WT). However, four weeks postpartum, most PE-related renal pathologies were absent, including albuminuria and elevated biomarker expression. Only mild enlargement of the glomerular tuft could be detected. Overall, the glomerular and tubular function were affected during pregnancy in the transgenic PE rat. However, almost all these pathologies observed during PE recovered postpartum. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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18 pages, 2783 KiB

Open AccessArticle

Association Analysis in Children Born from Normal and Complicated Pregnancies—Cardiovascular Disease Associated microRNAs and the Incidence of Prehypertension/Hypertension, Overweight/Obesity, Valve Problems and Heart Defects

by Ilona Hromadnikova, Katerina Kotlabova, Ladislav Krofta and Jan Sirc

Int. J. Mol. Sci. 2020, 21(21), 8413; https://doi.org/10.3390/ijms21218413 - 9 Nov 2020

Cited by 5 | Viewed by 2815

Abstract

The goal was to assess how a history of any kind of pregnancy-related complication altered expression profile of microRNAs played a role in the pathogenesis of diabetes, cardiovascular and cerebrovascular diseases in the peripheral blood leukocytes of children at the age of 3–11 [...] Read more.

The goal was to assess how a history of any kind of pregnancy-related complication altered expression profile of microRNAs played a role in the pathogenesis of diabetes, cardiovascular and cerebrovascular diseases in the peripheral blood leukocytes of children at the age of 3–11 years. The prior exposure to gestational hypertension, preeclampsia, fetal growth restriction, gestational diabetes mellitus, preterm prelabor rupture of membranes or spontaneous preterm birth causes that a significant proportion of children (57.42% to 90.0% specifically) had a substantially altered microRNA expression profile, which might be the origin of a lifelong cardiovascular risk. A total of 23 out of 29 tested microRNAs were upregulated in children born from such complicated gestation. The occurrence of overweight, obesity, valve problems and heart defects even intensified upregulation of microRNAs already present in children exposed to such pregnancy complications. The occurrence of overweight/obesity (miR-92a-3p, and miR-210-3p) and valve problems or heart defects (miR-342-3p) induced microRNA upregulation in children affected with pregnancy complications. Overall, 42.86% overweight/obese children and 27.36% children with valve problems or heart defects had even higher microRNA levels than children with normal clinical findings after complicated pregnancies. In addition, the microRNA expression profile was also able to differentiate between children descending from normal gestation in relation to the occurrence of overweight and obesity. Screening on the base of the combination of 19 microRNAs identified 70.0% overweight/obese children at 90.0% specificity. In general, children after complicated pregnancies, just as children after normal pregnancies, with abnormal findings are at a higher risk of the onset of cardiovascular complications, and their dispensarization, with the aim to implement primary prevention strategies, would be beneficial. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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15 pages, 4661 KiB

Open AccessArticle

Sex Specific Expression of Interleukin 7, 8 and 15 in Placentas of Women with Gestational Diabetes

by Simon Keckstein, Sophia Pritz, Niklas Amann, Sarah Meister, Susanne Beyer, Magdalena Jegen, Christina Kuhn, Stefan Hutter, Julia Knabl, Sven Mahner, Thomas Kolben, Udo Jeschke and Theresa M. Kolben

Int. J. Mol. Sci. 2020, 21(21), 8026; https://doi.org/10.3390/ijms21218026 - 28 Oct 2020

Cited by 22 | Viewed by 3492

Abstract

Gestational diabetes mellitus (GDM) is known to increase the risk for feto-maternal complications during pregnancy. A state of low-grade inflammation, with elevated levels of proinflammatory molecules, similar to patients with obesity or diabetes mellitus type 2 has also been partly described in GDM. [...] Read more.

Gestational diabetes mellitus (GDM) is known to increase the risk for feto-maternal complications during pregnancy. A state of low-grade inflammation, with elevated levels of proinflammatory molecules, similar to patients with obesity or diabetes mellitus type 2 has also been partly described in GDM. The placenta, as unique interface between mother and fetus, is not only passively affected by changes in one of these organisms, but also acts as a modulator by expressing hormones and cytokines. This study aimed to investigate the expression of the proinflammatory cytokines Interleukin (IL) 7, 8 and 15 in GDM in placental tissue. A total number of 80 placentas were included (40 GDM/40 control group). The expression of IL-7, 8 and 15 was investigated in extravillous trophoblast (EVT) and syncytiotrophoblast (SCT) by immunohistochemistry and immunofluorescence double staining. The immunohistochemical staining was evaluated with the semiquanitfied immunoreactive score (IRS). While the expression IL-15 was significantly upregulated in EVTs of women with GDM. The expression of IL-8 was significantly decreased in EVT of the GDM group. Furthermore, significant fetal sex specific differences were detectable in all three cytokines. Our findings suggest an involvement of the investigated cytokines in the maintenance of a state of chronic low-grade inflammation on placental level in patients suffering from GDM. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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22 pages, 2032 KiB

Open AccessArticle

Associations of Arginine with Gestational Diabetes Mellitus in a Follow-Up Study

by Izabela Burzynska-Pedziwiatr, Adrian Jankowski, Konrad Kowalski, Przemyslaw Sendys, Andrzej Zieleniak, Katarzyna Cypryk, Monika Zurawska-Klis, Lucyna A. Wozniak and Malgorzata Bukowiecka-Matusiak

Int. J. Mol. Sci. 2020, 21(21), 7811; https://doi.org/10.3390/ijms21217811 - 22 Oct 2020

Cited by 13 | Viewed by 2876

Abstract

In the reported study we applied the targeted metabolomic profiling employing high pressure liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC–MS/MS) to understand the pathophysiology of gestational diabetes mellitus (GDM), early identification of women who are at risk of developing GDM, [...] Read more.

In the reported study we applied the targeted metabolomic profiling employing high pressure liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC–MS/MS) to understand the pathophysiology of gestational diabetes mellitus (GDM), early identification of women who are at risk of developing GDM, and the differences in recovery postpartum between these women and normoglycemic women. We profiled the peripheral blood from patients during the second trimester of pregnancy and three months, and one year postpartum. In the GDM group Arg, Gln, His, Met, Phe and Ser were downregulated with statistical significance in comparison to normoglycemic (NGT) women. From the analysis of the association of all amino acid profiles of GDM and NGT women, several statistical models predicting diabetic status were formulated and compared with the literature, with the arginine-based model as the most promising of the screened ones (area under the curve (AUC) = 0.749). Our research results have shed light on the critical role of arginine in the development of GDM and may help in precisely distinguishing between GDM and NGT and earlier detection of GDM but also in predicting women with the increased type 2 diabetes mellitus (T2DM) risk. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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11 pages, 1109 KiB

Open AccessArticle

Gestational Diabetes Type 2: Variation in High-Density Lipoproteins Composition and Function

by Yael Pasternak, Tal Biron-Shental, Meital Ohana, Yael Einbinder, Nissim Arbib, Sydney Benchetrit and Tali Zitman-Gal

Int. J. Mol. Sci. 2020, 21(17), 6281; https://doi.org/10.3390/ijms21176281 - 30 Aug 2020

Cited by 10 | Viewed by 3030

Abstract

Aims: Class A2 gestational diabetes mellitus (GDMA2) has short- and long-term effects on the mother and child. These may include abnormalities of placentation, damage to endothelial cells and cardiovascular disease. This research investigated the function and composition of high-density lipoproteins (HDL) among women [...] Read more.

Aims: Class A2 gestational diabetes mellitus (GDMA2) has short- and long-term effects on the mother and child. These may include abnormalities of placentation, damage to endothelial cells and cardiovascular disease. This research investigated the function and composition of high-density lipoproteins (HDL) among women with GDMA2 and their fetuses. Methods: Thirty pregnant women were recruited during admission for delivery. The function and expression of HDL, paraoxonase1 (PON1) and apolipoprotein A1 (APOA1) in the blood samples and the placental tissue were evaluated. The effect of HDL on migration of endothelial cells was measured in vitro. Results: Compared to normal pregnancy (NP), APOA1 in the maternal plasma of women with GDMA2 was decreased. More APOA1 and PON1 were released from HDL of women with GDMA2, compared to NP. Placental APOA1 and PON1 were decreased in GDMA2. For endothelial cells stimulated with TNFα, HDL cell migration was decreased when cells were evaluated with NP-HDL, as compared to GDMA2-HDL. Conclusions: GDMA2 affects the composition and function of HDL in plasma. Changes in HDL commonly seen in GDMA2 were observed in maternal and placental samples, but not in cord samples. These results might indicate a placental role in protecting the fetus by preserving the components and functions of HDL and require further investigation. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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10 pages, 578 KiB

Open AccessArticle

Association of Maternal Regulatory Single Nucleotide Polymorphic CD99 Genotype with Preeclampsia in Pregnancies Carrying Male Fetuses in Ethiopian Women

by Tsehayneh Kelemu, Lena Erlandsson, Daniel Seifu, Markos Abebe, Sisay Teklu, Jill R. Storry and Stefan R. Hansson

Int. J. Mol. Sci. 2020, 21(16), 5837; https://doi.org/10.3390/ijms21165837 - 14 Aug 2020

Cited by 9 | Viewed by 2989

Abstract

Preeclampsia (PE) is a human specific syndrome with unknown etiology causing maternal and fetal morbidities and mortalities. In PE, maternal inflammatory responses are more exaggerated if the fetus is male than female. Other pregnancy complications such as spontaneous abortions are also more common [...] Read more.

Preeclampsia (PE) is a human specific syndrome with unknown etiology causing maternal and fetal morbidities and mortalities. In PE, maternal inflammatory responses are more exaggerated if the fetus is male than female. Other pregnancy complications such as spontaneous abortions are also more common if the fetus is male. Recent transcriptome findings showed an increased expression of CD99 in erythroid cells from male cord blood in PE. The single nucleotide polymorphism (SNP) rs311103, located in a GATA-binding site in a regulatory region on the X/Y chromosomes, governs a coordinated expression of the Xg blood group members CD99 and Xg^a in hematopoietic cells in a sex-dependent fashion. The rs311103C disrupts the GATA-binding site, resulting in decreased CD99 expression. We aimed to investigate the association between PE and the allele frequency of rs311103 in pregnancies in a fetal sex-dependent fashion. In a case-controlled study, we included 241 pregnant women, i.e., 105 PE cases and 136 normotensive controls. A SNP allelic discrimination analysis was performed on DNA from maternal venous blood and fetal cord blood by qPCR. A statistically significant association was observed between rs311103 allele frequency and PE in mothers carrying male fetuses. Therefore, the rs311103 genotype may play a role in the pathogenesis of PE in a fetal sex-specific manner. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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Review

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21 pages, 37896 KiB

Open AccessReview

On Placental Toxicology Studies and Cerium Dioxide Nanoparticles

by Gaëlle Deval, Sonja Boland, Thierry Fournier and Ioana Ferecatu

Int. J. Mol. Sci. 2021, 22(22), 12266; https://doi.org/10.3390/ijms222212266 - 12 Nov 2021

Cited by 9 | Viewed by 5180

Abstract

The human placenta is a transient organ essential for pregnancy maintenance, fetal development and growth. It has several functions, including that of a selective barrier against pathogens and xenobiotics from maternal blood. However, some pollutants can accumulate in the placenta or pass through [...] Read more.

The human placenta is a transient organ essential for pregnancy maintenance, fetal development and growth. It has several functions, including that of a selective barrier against pathogens and xenobiotics from maternal blood. However, some pollutants can accumulate in the placenta or pass through with possible repercussions on pregnancy outcomes. Cerium dioxide nanoparticles (CeO₂ NPs), also termed nanoceria, are an emerging pollutant whose impact on pregnancy is starting to be defined. CeO₂ NPs are already used in different fields for industrial and commercial applications and have even been proposed for some biomedical applications. Since 2010, nanoceria have been subject to priority monitoring by the Organization for Economic Co-operation and Development in order to assess their toxicity. This review aims to summarize the current methods and models used for toxicology studies on the placental barrier, from the basic ones to the very latest, as well as to overview the most recent knowledge of the impact of CeO₂ NPs on human health, and more specifically during the sensitive window of pregnancy. Further research is needed to highlight the relationship between environmental exposure to CeO₂ and placental dysfunction with its implications for pregnancy outcome. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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16 pages, 1814 KiB

Open AccessReview

Periodontitis and Gestational Diabetes Mellitus: A Potential Inflammatory Vicious Cycle

by María José Bendek, Gisela Canedo-Marroquín, Ornella Realini, Ignacio N. Retamal, Marcela Hernández, Anilei Hoare, Dolores Busso, Lara J. Monteiro, Sebastián E. Illanes and Alejandra Chaparro

Int. J. Mol. Sci. 2021, 22(21), 11831; https://doi.org/10.3390/ijms222111831 - 31 Oct 2021

Cited by 24 | Viewed by 8510

Abstract

Periodontitis is a chronic inflammatory immune disease associated with a dysbiotic state, influenced by keystone bacterial species responsible for disrupting the periodontal tissue homeostasis. Furthermore, the severity of periodontitis is determined by the interaction between the immune cell response in front of periodontitis-associated [...] Read more.

Periodontitis is a chronic inflammatory immune disease associated with a dysbiotic state, influenced by keystone bacterial species responsible for disrupting the periodontal tissue homeostasis. Furthermore, the severity of periodontitis is determined by the interaction between the immune cell response in front of periodontitis-associated species, which leads to the destruction of supporting periodontal tissues and tooth loss in a susceptible host. The persistent bacterial challenge induces modifications in the permeability and ulceration of the sulcular epithelium, which facilitates the systemic translocation of periodontitis-associated bacteria into distant tissues and organs. This stimulates the secretion of pro-inflammatory molecules and a chronic activation of immune cells, contributing to a systemic pro-inflammatory status that has been linked with a higher risk of several systemic diseases, such as type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM). Although periodontitis and GDM share the common feature of systemic inflammation, the molecular mechanistic link of this association has not been completely clarified. This review aims to examine the potential biological mechanisms involved in the association between periodontitis and GDM, highlighting the contribution of both diseases to systemic inflammation and the role of new molecular participants, such as extracellular vesicles and non-coding RNAs, which could act as novel molecular intercellular linkers between periodontal and placental tissues. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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26 pages, 1152 KiB

Open AccessReview

Novel Biomolecules in the Pathogenesis of Gestational Diabetes Mellitus

by Monika Ruszała, Magdalena Niebrzydowska, Aleksandra Pilszyk, Żaneta Kimber-Trojnar, Marcin Trojnar and Bożena Leszczyńska-Gorzelak

Int. J. Mol. Sci. 2021, 22(21), 11578; https://doi.org/10.3390/ijms222111578 - 27 Oct 2021

Cited by 23 | Viewed by 6288

Abstract

Gestational diabetes mellitus (GDM) is one of the most common metabolic diseases in pregnant women. Its early diagnosis seems to have a significant impact on the developing fetus, the course of delivery, and the neonatal period. It may also affect the later stages [...] Read more.

Gestational diabetes mellitus (GDM) is one of the most common metabolic diseases in pregnant women. Its early diagnosis seems to have a significant impact on the developing fetus, the course of delivery, and the neonatal period. It may also affect the later stages of child development and subsequent complications in the mother. Therefore, the crux of the matter is to find a biopredictor capable of singling out women at risk of developing GDM as early as the very start of pregnancy. Apart from the well-known molecules with a proven and clear-cut role in the pathogenesis of GDM, e.g., adiponectin and leptin, a potential role of newer biomolecules is also emphasized. Less popular and less known factors with different mechanisms of action include: galectins, growth differentiation factor-15, chemerin, omentin-1, osteocalcin, resistin, visfatin, vaspin, irisin, apelin, fatty acid-binding protein 4 (FABP4), fibroblast growth factor 21, and lipocalin-2. The aim of this review is to present the potential and significance of these 13 less known biomolecules in the pathogenesis of GDM. It seems that high levels of FABP4, low levels of irisin, and high levels of under-carboxylated osteocalcin in the serum of pregnant women can be used as predictive markers in the diagnosis of GDM. Hopefully, future clinical trials will be able to determine which biomolecules have the most potential to predict GDM. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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14 pages, 607 KiB

Open AccessReview

Insight into the Key Points of Preeclampsia Pathophysiology: Uterine Artery Remodeling and the Role of MicroRNAs

by Katarzyna Pankiewicz, Anna Fijałkowska, Tadeusz Issat and Tomasz M. Maciejewski

Int. J. Mol. Sci. 2021, 22(6), 3132; https://doi.org/10.3390/ijms22063132 - 19 Mar 2021

Cited by 32 | Viewed by 4625

Abstract

Preeclampsia affects about 3–8% of all pregnancies. It represents a complex and multifaceted syndrome with at least several potential pathways leading to the development of disease. The main dogma in preeclampsia is the two-stage model of disease. Stage 1 (placental stage) takes place [...] Read more.

Preeclampsia affects about 3–8% of all pregnancies. It represents a complex and multifaceted syndrome with at least several potential pathways leading to the development of disease. The main dogma in preeclampsia is the two-stage model of disease. Stage 1 (placental stage) takes place in early pregnancy and is thought to be impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries that leads to reduced placental perfusion and release of numerous biological factors causing endothelial damage and development of acute maternal syndrome with systemic multiorgan failure (stage 2—the onset of maternal clinical symptoms, maternal stage). Recently, in the light of the vast body of evidence, two-stage model of preeclampsia has been updated with a few novel pathways leading to clinical manifestation in the second part of pregnancy. This paper reviews current state of knowledge about pathophysiology of preeclampsia and places particular focus on the recent advances in understanding of uterine artery remodeling alterations, as well as the role of microRNAs in preeclampsia. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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36 pages, 1018 KiB

Open AccessReview

Diabetes during Pregnancy: A Maternal Disease Complicating the Course of Pregnancy with Long-Term Deleterious Effects on the Offspring. A Clinical Review

by Asher Ornoy, Maria Becker, Liza Weinstein-Fudim and Zivanit Ergaz

Int. J. Mol. Sci. 2021, 22(6), 2965; https://doi.org/10.3390/ijms22062965 - 15 Mar 2021

Cited by 150 | Viewed by 17433

Abstract

In spite of the huge progress in the treatment of diabetes mellitus, we are still in the situation that both pregestational (PGDM) and gestational diabetes (GDM) impose an additional risk to the embryo, fetus, and course of pregnancy. PGDM may increase the rate [...] Read more.

In spite of the huge progress in the treatment of diabetes mellitus, we are still in the situation that both pregestational (PGDM) and gestational diabetes (GDM) impose an additional risk to the embryo, fetus, and course of pregnancy. PGDM may increase the rate of congenital malformations, especially cardiac, nervous system, musculoskeletal system, and limbs. PGDM may interfere with fetal growth, often causing macrosomia, but in the presence of severe maternal complications, especially nephropathy, it may inhibit fetal growth. PGDM may also induce a variety of perinatal complications such as stillbirth and perinatal death, cardiomyopathy, respiratory morbidity, and perinatal asphyxia. GDM that generally develops in the second half of pregnancy induces similar but generally less severe complications. Their severity is higher with earlier onset of GDM and inversely correlated with the degree of glycemic control. Early initiation of GDM might even cause some increase in the rate of congenital malformations. Both PGDM and GDM may cause various motor and behavioral neurodevelopmental problems, including an increased incidence of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Most complications are reduced in incidence and severity with the improvement in diabetic control. Mechanisms of diabetic-induced damage in pregnancy are related to maternal and fetal hyperglycemia, enhanced oxidative stress, epigenetic changes, and other, less defined, pathogenic mechanisms. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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15 pages, 1682 KiB

Open AccessReview

Pathophysiology of Preeclampsia: The Role of Exosomes

by Keiichi Matsubara, Yuko Matsubara, Yuka Uchikura and Takashi Sugiyama

Int. J. Mol. Sci. 2021, 22(5), 2572; https://doi.org/10.3390/ijms22052572 - 4 Mar 2021

Cited by 47 | Viewed by 9759

Abstract

The pathogenesis of preeclampsia begins when a fertilized egg infiltrates the decidua, resulting in implantation failure (e.g., due to extravillous trophoblast infiltration disturbance and abnormal spiral artery remodeling). Thereafter, large amounts of serum factors (e.g., soluble fms-like tyrosine kinase 1 and soluble endoglin) [...] Read more.

The pathogenesis of preeclampsia begins when a fertilized egg infiltrates the decidua, resulting in implantation failure (e.g., due to extravillous trophoblast infiltration disturbance and abnormal spiral artery remodeling). Thereafter, large amounts of serum factors (e.g., soluble fms-like tyrosine kinase 1 and soluble endoglin) are released into the blood from the hypoplastic placenta, and preeclampsia characterized by multiorgan disorder caused by vascular disorders develops. Successful implantation and placentation require immune tolerance to the fertilized egg as a semi-allograft and the stimulation of extravillous trophoblast infiltration. Recently, exosomes with diameters of 50–100 nm have been recognized to be involved in cell–cell communication. Exosomes affect cell functions in autocrine and paracrine manners via their encapsulating microRNA/DNA and membrane-bound proteins. The microRNA profiles of blood exosomes have been demonstrated to be useful for the evaluation of preeclampsia pathophysiology and prediction of the disease. In addition, exosomes derived from mesenchymal stem cells have been found to have cancer-suppressing effects. These exosomes may repair the pathophysiology of preeclampsia through the suppression of extravillous trophoblast apoptosis and promotion of these cells’ invasive ability. Exosomes secreted by various cells have received much recent attention and may be involved in the maintenance of pregnancy and pathogenesis of preeclampsia. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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19 pages, 3201 KiB

Open AccessReview

Role of the Macrophage Migration Inhibitory Factor in the Pathophysiology of Pre-Eclampsia

by Tullia Todros, Luana Paulesu, Simona Cardaropoli, Alessandro Rolfo, Bianca Masturzo, Leonardo Ermini, Roberta Romagnoli and Francesca Ietta

Int. J. Mol. Sci. 2021, 22(4), 1823; https://doi.org/10.3390/ijms22041823 - 12 Feb 2021

Cited by 9 | Viewed by 3507

Abstract

Proinflammatory cytokines are produced in pregnancy in response to the invading pathogens and/or nonmicrobial causes such as damage-associated molecules and embryonic semi-allogenic antigens. While inflammation is essential for a successful pregnancy, an excessive inflammatory response is implicated in several pathologies including pre-eclampsia (PE). [...] Read more.

Proinflammatory cytokines are produced in pregnancy in response to the invading pathogens and/or nonmicrobial causes such as damage-associated molecules and embryonic semi-allogenic antigens. While inflammation is essential for a successful pregnancy, an excessive inflammatory response is implicated in several pathologies including pre-eclampsia (PE). This review focuses on the proinflammatory cytokine macrophage migration inhibitory factor (MIF), a critical regulator of the innate immune response and a major player of processes allowing normal placental development. PE is a severe pregnancy-related syndrome characterized by exaggerated inflammatory response and generalized endothelial damage. In some cases, usually of early onset, it originates from a maldevelopment of the placenta, and is associated with intrauterine growth restriction (IUGR) (placental PE). In other cases, usually of late onset, pre-pregnancy maternal diseases represent risk factors for the development of the disease (maternal PE). Available data suggest that low MIF production in early pregnancy could contribute to the abnormal placentation. The resulting placental hypoxia in later pregnancy could produce high release of MIF in maternal serum typical of placental PE. More studies are needed to understand the role of MIF, if any, in maternal PE. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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19 pages, 1127 KiB

Open AccessReview

The Role of Arachidonic and Linoleic Acid Derivatives in Pathological Pregnancies and the Human Reproduction Process

by Małgorzata Szczuko, Justyna Kikut, Natalia Komorniak, Jacek Bilicki, Zbigniew Celewicz and Maciej Ziętek

Int. J. Mol. Sci. 2020, 21(24), 9628; https://doi.org/10.3390/ijms21249628 - 17 Dec 2020

Cited by 101 | Viewed by 11830

Abstract

The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to reproduction and pregnancy. Arachidonic (AA) and linoleic acid (LA) derivatives play important roles in human fertility [...] Read more.

The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to reproduction and pregnancy. Arachidonic (AA) and linoleic acid (LA) derivatives play important roles in human fertility and the course of pathological pregnancies. Recent studies have demonstrated that uncontrolled inflammation has a significant impact on reproduction, spermatogenesis, endometriosis, polycystic ovary syndrome (PCOS) genesis, implantation, pregnancy and labor. In addition, cyclooxygenase-mediated prostaglandins and AA metabolite levels are higher in women’s ovarian tissue when suffering from PCOS. It has been demonstrated that abnormal cyclooxygenase-2 (COX-2) levels are associated with ovulation failure, infertility, and implantation disorders and the increase in 9-HODE/13-HODE was a feature recognized in PCOS patients. Maintaining inflammation without neutrophil participation allows pregnant women to tolerate the fetus, while excessive inflammatory activation may lead to miscarriages and other pathological complications in pregnancies. Additionally AA and LA derivatives play an important role in pregnancy pathologies, e.g., gestational diabetes mellitus, preeclampsia (PE), and fetal growth, among others. The pathogenesis of PE and other pathological states in pregnancy involving eicosanoids have not been fully identified. A significant expression of 15-LOX-1,2 was found in women with PE, leading to an increase in the synthesis of AA and LA derivatives, such as hydroxyeicozatetraenoic acids (HETE) and hydroxyoctadecadiene acids (HODE). Synthesis of the metabolites 5-, 8-, 12-, and 15-HETE increased in the placenta, while 20-HETE increased only in umbilical cord blood in women with preeclampsia compared to normal pregnancies. In obese women with gestational diabetes mellitus (GDM) an increase in epoxygenase products in the cytochrome P450 (CYP) and the level of 20-HETE associated with the occurrence of insulin resistance (IR) were found. In addition, 12- and 20-HETE levels were associated with arterial vasoconstriction and epoxyeicosatrienoic acids (EETs) with arterial vasodilatation and uterine relaxation. Furthermore, higher levels of 5- and 15-HETE were associated with premature labor. By analyzing the influence of free fatty acids (FFA) and their derivatives on male reproduction, it was found that an increase in the AA in semen reduces its amount and the ratio of omega-6 to omega-3 fatty acids showed higher values in infertile men compared to the fertile control group. There are several studies on the role of HETE/HODE in relation to male fertility. 15-Hydroperoxyeicosatetraenoic acid may affect the integrity of the membrane and sperm function. Moreover, the incubation of sperm with physiologically low levels of prostaglandins (PGE2/PGF2α) improves the functionality of human sperm. Undoubtedly, these problems are still insufficiently understood and require further research. However, HETE and HODE could serve as predictive and diagnostic biomarkers for pregnancy pathologies (especially in women with risk factors for overweight and obesity). Such knowledge may be helpful in finding new treatment strategies for infertility and the course of high-risk pregnancies. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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23 pages, 2041 KiB

Open AccessReview

The Cervicovaginal Mucus Barrier

by Guillaume Lacroix, Valérie Gouyer, Frédéric Gottrand and Jean-Luc Desseyn

Int. J. Mol. Sci. 2020, 21(21), 8266; https://doi.org/10.3390/ijms21218266 - 4 Nov 2020

Cited by 76 | Viewed by 13682

Abstract

Preterm births are a global health priority that affects 15 million babies every year worldwide. There are no effective prognostic and therapeutic strategies relating to preterm delivery, but uterine infections appear to be a major cause. The vaginal epithelium is covered by the [...] Read more.

Preterm births are a global health priority that affects 15 million babies every year worldwide. There are no effective prognostic and therapeutic strategies relating to preterm delivery, but uterine infections appear to be a major cause. The vaginal epithelium is covered by the cervicovaginal mucus, which is essential to health because of its direct involvement in reproduction and functions as a selective barrier by sheltering the beneficial lactobacilli while helping to clear pathogens. During pregnancy, the cervical canal is sealed with a cervical mucus plug that prevents the vaginal flora from ascending toward the uterine compartment, which protects the fetus from pathogens. Abnormalities of the cervical mucus plug and bacterial vaginosis are associated with a higher risk of preterm delivery. This review addresses the current understanding of the cervicovaginal mucus and the cervical mucus plug and their interactions with the microbial communities in both the physiological state and bacterial vaginosis, with a focus on gel-forming mucins. We also review the current state of knowledge of gel-forming mucins contained in mouse cervicovaginal mucus and the mouse models used to study bacterial vaginosis. Full article

(This article belongs to the Special Issue Pathogenesis of Pregnancy-Related Complications 2.0)

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