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Impact of Endogenic and Exogenic Oxidative Stress Triggers on Pregnant Woman, Fetus, and Child

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 31961

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Guest Editor
1. Clinical Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, Zaloška c. 2., 1000 Ljubljana, Slovenia
2. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
Interests: pregnancy complications; screening for Down syndrome; autism spectrum disorders; tumor markers
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Special Issue Information

Dear Colleagues,

In all living organisms, there is a delicate balance between oxidation caused by reactive species (RS, also called free radicals) and antioxidant defense. A shift in this balance is the cause of a condition known as “oxidative stress” (OS), which can cause cellular damage that eventually leads to premature aging and many diseases. Oxidative stress is not actually a “disease” and does not show a specific clinical picture, but it hides behind the symptoms and signs of the underlying disease. In other words, we can only measure it if we perform certain biochemical tests. These tests can be set for different biological samples.

Pregnancy is a dynamic process during which systemic and local changes occur in the mother. All these changes are necessary for the normal development of the fetus. Disorders in this process can lead to complications in pregnancy, changes in the growth path of the fetus, premature birth, and some other conditions (e.g., treatment of preeclampsia and gestational diabetes or the need for caesarean section), intrauterine growth restriction (IUGR), and small or large infants for gestational age.

Homeostasis of the maternal environment is maintained through a variety of mediators, including hormones, cytokines, oxidative status, and diet. Factors that interfere with this homeostasis can be endogenous or exogenous and are inflammation, oxidative stress, exposure to chemical agents, and lack or excess of food, which can jeopardize the growth and development of the fetus. During pregnancy, there is an increase in oxidative stress, a phenomenon caused by the usual systemic inflammatory response, resulting in a large amount of reactive oxygen species in the circulation. The development and maturation of the placenta is a complex process that requires coordinated regulation of trophoblast invasion and its differentiation and spread in the maternal decidua.

This Special Issue is dedicated to all aspects of oxidative stress. We must take into account all extensions of oxidative stress, which also include the period before fertilization itself, and the entire duration of pregnancy and childbirth. However, we know that oxidative stress during pregnancy can lead to the development of certain disorders even in the later development of the child. When considering your submission, please keep in mind that IJMS is a journal of molecular science. However, submissions of clinical studies that include biomolecular experiments or pathological research with case sample data are welcomed.

Prof. Dr. Joško Osredkar
Guest Editor

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Keywords

  • oxidative stress
  • angiogenesis
  • hypertension in pregnancy
  • preterm birth
  • metabolic syndrome
  • biomarkers
  • toxic agents
  • follicular fluid
  • amniotic fluid
  • cord blood

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Published Papers (9 papers)

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Editorial

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5 pages, 180 KiB  
Editorial
Impact of Endogenic and Exogenic Oxidative Stress Triggers on Pregnant Woman, Fetus, and Child
by Joško Osredkar
Int. J. Mol. Sci. 2023, 24(6), 5958; https://doi.org/10.3390/ijms24065958 - 22 Mar 2023
Cited by 1 | Viewed by 1248
Abstract
In all living organisms, there is a delicate balance between oxidation caused by reactive species (RS, also called free radicals) and antioxidant defence [...] Full article

Research

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14 pages, 1095 KiB  
Article
Altered Thermal Behavior of Blood Plasma Proteome Related to Inflammatory Cytokines in Early Pregnancy Loss
by Regina Komsa-Penkova, Avgustina Danailova, Sashka Krumova, Galya Georgieva, Ina Giosheva, Lidia Gartcheva, Ivan Iliev, Emil Gartchev, Kameliya Kercheva, Alexey Savov and Svetla Todinova
Int. J. Mol. Sci. 2022, 23(15), 8764; https://doi.org/10.3390/ijms23158764 - 6 Aug 2022
Cited by 6 | Viewed by 2240
Abstract
Early pregnancy loss (EPL) is a relatively common pathology of which almost 50% of cases remain idiopathic. In the search for novel biomarkers, differential scanning calorimetry (DSC) is intensively used to characterize the thermodynamic behavior of blood plasma/serum proteome in health and disease. [...] Read more.
Early pregnancy loss (EPL) is a relatively common pathology of which almost 50% of cases remain idiopathic. In the search for novel biomarkers, differential scanning calorimetry (DSC) is intensively used to characterize the thermodynamic behavior of blood plasma/serum proteome in health and disease. Herein, for the first time, we investigate the DSC denaturation profiles of blood plasma derived from patients suffering EPL compared to healthy pregnant and non-pregnant women. Data analysis reveals that 58% of the EPL thermograms differ significantly from those of healthy pregnant women. Thermal stabilization of a fraction of albumin-assigned transition with concomitant suppression of the major and enhancement of the globulin-assigned transition are characteristic features of EPL calorimetric profiles that could be used as a new indicator of a risk pregnancy. The presented results suggest an altered composition or intermolecular interactions of the plasma proteome of women with EPL. In addition, the alterations of the EPL thermograms correlate with the increased blood levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and a higher prevalence of the polymorphism in the plasminogen activator inhibitor type-1 (PAI-1) gene, suggesting an expression of an overall enhanced immune response. The concomitant changes in plasma thermograms confirm the potential of the DSC approach for distinguishing changes in the pathological state of the blood plasma proteome. Full article
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15 pages, 2667 KiB  
Article
Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma
by Yasmin Abedin, Sofia Gabrilovich, Emily Alpert, Erica Rego, Salma Begum, Qingshi Zhao, Debra Heller, Mark H. Einstein and Nataki C. Douglas
Int. J. Mol. Sci. 2022, 23(11), 5980; https://doi.org/10.3390/ijms23115980 - 26 May 2022
Cited by 7 | Viewed by 2991
Abstract
Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch [...] Read more.
Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy. Full article
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15 pages, 2500 KiB  
Article
Dysregulation of Oxygen Sensing/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia
by Sharon A. McCracken, Sean K. M. Seeho, Tamara Carrodus, Jenny H. Park, Narelle Woodland, Eileen D. M. Gallery, Jonathan M. Morris and Anthony W. Ashton
Int. J. Mol. Sci. 2022, 23(5), 2772; https://doi.org/10.3390/ijms23052772 - 2 Mar 2022
Cited by 9 | Viewed by 2731
Abstract
Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. [...] Read more.
Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1α and HIF-2α are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-α-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel–Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-α-subunits is defective. This is associated with enhanced VHL/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases. Full article
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12 pages, 1313 KiB  
Article
Intrauterine Nitric Oxide Deficiency Weakens Differentiation of Vascular Smooth Muscle in Newborn Rats
by Anastasia A. Shvetsova, Anna A. Borzykh, Ekaterina K. Selivanova, Oxana O. Kiryukhina, Dina K. Gaynullina and Olga S. Tarasova
Int. J. Mol. Sci. 2021, 22(15), 8003; https://doi.org/10.3390/ijms22158003 - 27 Jul 2021
Cited by 6 | Viewed by 2101
Abstract
Nitric oxide (NO) deficiency during pregnancy is a key reason for preeclampsia development. Besides its important vasomotor role, NO is shown to regulate the cell transcriptome. However, the role of NO in transcriptional regulation of developing smooth muscle has never been studied before. [...] Read more.
Nitric oxide (NO) deficiency during pregnancy is a key reason for preeclampsia development. Besides its important vasomotor role, NO is shown to regulate the cell transcriptome. However, the role of NO in transcriptional regulation of developing smooth muscle has never been studied before. We hypothesized that in early ontogeny, NO is important for the regulation of arterial smooth muscle-specific genes expression. Pregnant rats consumed NO-synthase inhibitor L-NAME (500 mg/L in drinking water) from gestational day 10 till delivery, which led to an increase in blood pressure, a key manifestation of preeclampsia. L-NAME reduced blood concentrations of NO metabolites in dams and their newborn pups, as well as relaxations of pup aortic rings to acetylcholine. Using qPCR, we demonstrated reduced abundances of the smooth muscle-specific myosin heavy chain isoform, α-actin, SM22α, and L-type Ca2+-channel mRNAs in the aorta of newborn pups from the L-NAME group compared to control pups. To conclude, the intrauterine NO deficiency weakens gene expression specific for a contractile phenotype of arterial smooth muscle in newborn offspring. Full article
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Review

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9 pages, 1041 KiB  
Review
Oxidative Stress as a Potential Underlying Cause of Minimal and Mild Endometriosis-Related Infertility
by Gabija Didziokaite, Gabija Biliute, Jogaile Gudaite and Violeta Kvedariene
Int. J. Mol. Sci. 2023, 24(4), 3809; https://doi.org/10.3390/ijms24043809 - 14 Feb 2023
Cited by 24 | Viewed by 5295
Abstract
Oxidative stress (OS) plays an important role in a variety of physiological and pathological processes of the female reproductive system. In recent years the relationship between OS and endometriosis has been of particular interest, and a theory has been suggested that OS may [...] Read more.
Oxidative stress (OS) plays an important role in a variety of physiological and pathological processes of the female reproductive system. In recent years the relationship between OS and endometriosis has been of particular interest, and a theory has been suggested that OS may be a cause of endometriosis development. While the link between endometriosis and infertility is well established, minimal or mild stages of endometriosis are not considered to cause infertility. Increasing evidence of OS as a leading agent in the development of endometriosis has brought up a theory of minimal/mild endometriosis itself being one of the manifestations of high OS rather than a separate disease which directly causes infertility. Moreover, further development of the disease is thought to contribute to an increased production of reactive oxygen species (ROS) thus leading to the progression of endometriosis itself as well as to other pathological processes in the female reproductive system. Therefore, in case of minimal or mild endometriosis, the less invasive treatment could be offered in order to stop the ongoing cycle of endometriosis-reinforced excess ROS production and to reduce their harmful effects. In this article the existing connection between OS, endometriosis, and infertility is explored. Full article
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14 pages, 1135 KiB  
Review
The Significance of COVID-19 Diseases in Lipid Metabolism Pregnancy Women and Newborns
by Miljana Z. Jovandaric, Milan Dokic, Ivana R. Babovic, Srboljub Milicevic, Jelena Dotlic, Branislav Milosevic, Miljan Culjic, Luka Andric, Nemanja Dimic, Olga Mitrovic, Aleksandra Beleslin, Jovana Nikolic, Zorica Jestrovic and Sandra Babic
Int. J. Mol. Sci. 2022, 23(23), 15098; https://doi.org/10.3390/ijms232315098 - 1 Dec 2022
Cited by 8 | Viewed by 2738
Abstract
Coronavirus disease (COVID-19) is an infectious disease caused by SARS-CoV-2. Elderly people, people with immunodeficiency, autoimmune and malignant diseases, as well as people with chronic diseases have a higher risk of developing more severe forms of the disease. Pregnant women and children can [...] Read more.
Coronavirus disease (COVID-19) is an infectious disease caused by SARS-CoV-2. Elderly people, people with immunodeficiency, autoimmune and malignant diseases, as well as people with chronic diseases have a higher risk of developing more severe forms of the disease. Pregnant women and children can becomesick, although more often they are only the carriers of the virus. Recent studies have indicated that infants can also be infected by SARS-CoV-2 and develop a severe form of the disease with a fatal outcome. Acute Respiratory Distress Syndrome (ARDS) ina pregnant woman can affect the supply of oxygen to the fetus and initiate the mechanism of metabolic disorders of the fetus and newborn caused by asphyxia. The initial metabolic response of the newborn to the lack of oxygen in the tissues is the activation of anaerobic glycolysis in the tissues and an increase in the concentration of lactate and ketones. Lipid peroxidation, especially in nerve cells, is catalyzed by iron released from hemoglobin, transferrin and ferritin, whose release is induced by tissue acidosis and free oxygen radicals. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through various pathways, resulting in a decrease in the antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in the cells, ultimately leading to oxidative cell stress, and finally, death. Conclusion: damage to the mitochondria as a result of lipid peroxidation caused by the COVID-19 disease can cause the death of a newborn and pregnant women as well as short time and long-time sequelae. Full article
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23 pages, 695 KiB  
Review
Maternal Distress during Pregnancy and the Postpartum Period: Underlying Mechanisms and Child’s Developmental Outcomes—A Narrative Review
by Ljiljana Jeličić, Aleksandra Veselinović, Milica Ćirović, Vladimir Jakovljević, Saša Raičević and Miško Subotić
Int. J. Mol. Sci. 2022, 23(22), 13932; https://doi.org/10.3390/ijms232213932 - 11 Nov 2022
Cited by 11 | Viewed by 8502
Abstract
Maternal mental health may be considered a determining factor influencing fetal and child development. An essential factor with potentially negative consequences for a child’s psychophysiological development is the presence of maternal distress during pregnancy and the postpartum period. The review is organized and [...] Read more.
Maternal mental health may be considered a determining factor influencing fetal and child development. An essential factor with potentially negative consequences for a child’s psychophysiological development is the presence of maternal distress during pregnancy and the postpartum period. The review is organized and presented to explore and describe the effects of anxiety, stress, and depression in pregnancy and the postpartum period on adverse child developmental outcomes. The neurobiology of maternal distress and the transmission mechanisms at the molecular level to the fetus and child are noted. In addition, the paper discusses the findings of longitudinal studies in which early child development is monitored concerning the presence of maternal distress in pregnancy and the postpartum period. This topic gained importance in the COVID-19 pandemic context, during which a higher frequency of maternal psychological disorders was observed. The need for further interdisciplinary research on the relationship between maternal mental health and fetal/child development was highlighted, especially on the biological mechanisms underlying the transmission of maternal distress to the (unborn) child, to achieve positive developmental outcomes and improve maternal and child well-being. Full article
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14 pages, 697 KiB  
Review
Impact of Oxidative Stress on Molecular Mechanisms of Cervical Ripening in Pregnant Women
by Maciej W. Socha, Wojciech Flis, Mateusz Wartęga and Martyna Stankiewicz
Int. J. Mol. Sci. 2022, 23(21), 12780; https://doi.org/10.3390/ijms232112780 - 24 Oct 2022
Cited by 7 | Viewed by 2489
Abstract
Uterine cervix is one of the essential factors in labor and maintaining the proper course of pregnancy. During the last days of gestation, the cervix undergoes extensive changes manifested by transformation from a tight and rigid to one that is soft and able [...] Read more.
Uterine cervix is one of the essential factors in labor and maintaining the proper course of pregnancy. During the last days of gestation, the cervix undergoes extensive changes manifested by transformation from a tight and rigid to one that is soft and able to dilate. These changes can be summarized as “cervical ripening”. Changes in the cervical tissue can be referred to as remodeling of the extracellular matrix. The entire process is the result of a close relationship between biochemical and molecular pathways, which is strictly controlled by inflammatory and endocrine factors. When the production of reactive oxygen species exceeds the antioxidant capacity, oxidative stress occurs. A physiologic increase of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is observed through pregnancy. ROS play important roles as second messengers in many intracellular signaling cascades contributing to the course of gestation. This review considers their involvement in the cervical ripening process, emphasizing the molecular and biochemical pathways and the clinical implications. Full article
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