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Placental apoptosis increased by hypoxia inducible Factor-1 stabilization is counteracted by leptin.Biology of Reproduction Jun 2024During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of...
During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of hypoxia as modulator of trophoblast cell death. Previous reports have shown that leptin, a placental cytokine, promotes cell survival in both cell culture and placental explant models. The aim of this work is to establish the role of leptin in apoptosis under hypoxic condition in trophoblast cells. In this study, we evaluated the effect of cobalt chloride, a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1α), on Swan-71 and human placental explants. Hypoxia chamber was also used to generate 2% oxygen. Apoptosis was determined by the presence of apoptotic nucleus, fragmentation of DNA and Caspase-3 and PARP-1 cleavage. The pro-apoptotic proteins BAX, BID, BAD and BAK and the anti-apoptotic effectors BCL-2, BCL-xL and MCL-1 were also analyzed. We found that HIF-1α stabilization increased the appearance of apoptotic nucleus, fragmentation of DNA, and Caspase-3 and PARP-1 cleavage. Hypoxia mimicking conditions enhanced the expression of pro-apoptotic effectors BAX, BID, BAD and BAK. HIF-1α stabilization also downregulated the level of BCL-2, BCL-xL and MCL-1. All these apoptotic parameters changes were reversed with leptin treatment. Moreover, we showed that leptin action on apoptosis modulation involves PI3K and MAPK signaling pathways. Obtained data demonstrate that HIF-1α stabilization induces apoptosis in human placenta and leptin counteracts this effect, reinforcing its role as a survival cytokine.
PubMed: 38924703
DOI: 10.1093/biolre/ioae095 -
Advanced Science (Weinheim,... Jun 2024The placenta links feto-maternal circulation for exchanges of nutrients, gases, and metabolic wastes between the fetus and mother, being essential for pregnancy process...
The placenta links feto-maternal circulation for exchanges of nutrients, gases, and metabolic wastes between the fetus and mother, being essential for pregnancy process and maintenance. The allantois and mesodermal components of amnion, chorion, and yolk sac are derived from extraembryonic mesoderm (Ex-Mes), however, the mechanisms contributing to distinct components of the placenta and regulation the interactions between allantois and epithelium during chorioallantoic fusion and labyrinth formation remains unclear. Isl1 is expressed in progenitors of the Ex-Mes and allantois the Isl1 mut mouse line is analyzed to investigate contribution of Isl1 Ex-Mes / allantoic progenitors to cells of the allantois and placenta. This study shows that Isl1 identifies the Ex-Mes progenitors for endothelial and vascular smooth muscle cells, and most of the mesenchymal cells of the placenta and umbilical cord. Deletion of Isl1 causes defects in allantois growth, chorioallantoic fusion, and placenta vessel morphogenesis. RNA-seq and CUT&Tag analyses revealed that Isl1 promotes allantoic endothelial, inhibits mesenchymal cell differentiation, and allantoic signals regulated by Isl1 mediating the inductive interactions between the allantois and chorion critical for chorionic epithelium differentiation, villous formation, and labyrinth angiogenesis. This study above reveals that Isl1 plays roles in regulating multiple genetic and epigenetic pathways of vascular morphogenesis, provides the insight into the mechanisms for placental formation, highlighting the necessity of Isl1 for placenta formation/pregnant maintenance.
PubMed: 38923264
DOI: 10.1002/advs.202400238 -
BJOG : An International Journal of... Jun 2024Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains...
OBJECTIVE
Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes.
DESIGN
Superiority, double-blind randomised controlled trial.
SETTING
A total of 20 UK fetal medicine units.
POPULATION
Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22 and 29 weeks of gestation.
METHODS
Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation.
MAIN OUTCOME MEASURES
All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85.
RESULTS
In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm).
CONCLUSIONS
Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition.
PubMed: 38923115
DOI: 10.1111/1471-0528.17888 -
Toxins Jun 2024Mycotoxins are toxic secondary metabolites produced by various fungi that can contaminate food crops, which, in turn, may lead to human exposure. Chronic exposure to...
Mycotoxins are toxic secondary metabolites produced by various fungi that can contaminate food crops, which, in turn, may lead to human exposure. Chronic exposure to mycotoxins can cause adverse health effects including reproductive and developmental toxicity. Pregnant women and their foetuses present a vulnerable group for exposure to mycotoxins that can cross the placenta. Human biomonitoring of mycotoxins provides a real-life approach to estimate internal exposure. In this pilot study, 24-h urine samples from 36 pregnant Dutch women were analysed for aflatoxin M1 (AFM1), total deoxynivalenol (DON), de-epoxy-deoxynivalenol (DOM-1), total zearalenone (ZEN), total α-zearalenol (α-ZEL), total β-zearalenol (β-ZEL) and total zearalanone (ZAN), where 'total' refers to mycotoxins and their conjugated forms. Serum samples from these women were analysed for fumonisin B1 (FB1) and ochratoxin A (OTA). All samples were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The most prevalent mycotoxins were total DON, total ZEN and OTA, with a detection frequency of 100%. DOM-1, total α-ZEL and total β-ZEL were detected but to a lesser extent, while AFM1, total ZAN and FB1 were undetected. Median concentrations were 4.75 μg total DON/L, 0.0350 μg DOM-1/L, 0.0413 μg total ZEN/L, 0.0379 μg total α-ZEL/L, 0.0189 μg total β-ZEL/L, and 0.121 μg OTA/L. The calculated median concentration for total ZEN and its metabolites was 0.105 μg/L. Based on two separate risk assessment approaches, total DON exposure in this group was considered to be of low concern. Similarly, exposure to total ZEN and its metabolites in this group was of low concern. For OTA, the risk of non-neoplastic effects was of low concern based on exposure in this group, and the risk of neoplastic effects was of low concern in the majority of participants in this group. The findings of this pilot study confirm the presence of mycotoxins in the urine and serum of pregnant Dutch women, with total DON, total ZEN, and OTA most frequently detected. Exposure to all measured mycotoxins was considered to be of low concern in this group, except for exposure to OTA, which was of low concern for the majority of participants. The study's findings offer valuable insights but should be confirmed using a larger and more diverse sample of the Dutch general population.
Topics: Humans; Female; Mycotoxins; Biological Monitoring; Pregnancy; Adult; Netherlands; Pilot Projects; Risk Assessment; Young Adult; Tandem Mass Spectrometry; Maternal Exposure
PubMed: 38922172
DOI: 10.3390/toxins16060278 -
Veterinary Sciences May 2024There is a growing interest in the composition of amniotic fluid (AF) in both humans and animals. In addition to its nutritional and protective functions for the foetus,...
There is a growing interest in the composition of amniotic fluid (AF) in both humans and animals. In addition to its nutritional and protective functions for the foetus, current knowledge demonstrates that AF also serves advanced diagnostic, prognostic, and therapeutic roles. Newborn dogs have an underdeveloped immune system, making them highly susceptible to dangerous pathogens such as canine parvovirus (CPV-2), canine infectious hepatitis virus (CAdV-1), and canine distemper virus (CDV), thus exposing them to a high risk of mortality in the first weeks of life. Immunoglobulins G (IgGs) represent the only antibody isotype capable of crossing the placenta in a small amount and have been detected also in canine AF. The primary aim of this study was to investigate the reliability of AF collected at birth as a marker of passive immunity in canine species. For this purpose, total and specific IgGs against CPV-2, CAdV-1, and CDV were investigated and quantified in both maternal plasma and AF collected at the time of caesarean section. The vaccination status of the bitches was also taken into consideration. Since the immune system can be influenced by gestational age, with preterm infants having immature innate and adaptive immunity, IgG concentrations were correlated with amniotic lecithin, sphingomyelin, cortisol, surfactant protein A, and pentraxin 3 levels. In a previous study from our group on foetal maturity these molecules were measured in the same samples. Finally, correlations between their amniotic content and neonatal outcomes were investigated. This study demonstrates that AF analysis at birth can provide valuable insights into neonatal immunity in puppies, offering a non-invasive method to detect potential early health risks, for improved puppy care and management.
PubMed: 38921981
DOI: 10.3390/vetsci11060234 -
Pathogens (Basel, Switzerland) Jun 2024Schistosome egg deposition in pregnant women may affect the placenta of infected mothers and cause placental schistosomiasis (PS). Histopathological examination of... (Review)
Review
BACKGROUND
Schistosome egg deposition in pregnant women may affect the placenta of infected mothers and cause placental schistosomiasis (PS). Histopathological examination of placental tissue is an inadequate detection method due to low sensitivity. So far, there has not been any systematic review on PS.
METHODS
We conducted a systematic literature search on PubMed, EMBASE, and Medline and included all publications that reported microscopically confirmed cases of PS, as well as the relevant secondary literature found in the citations of the primarily included publications.
RESULTS
Out of 113 abstracts screened we found a total of 8 publications describing PS with a total of 92 cases describing egg deposition of dead and/or viable eggs and worms of and in placental tissue. One cross-sectional study investigating the prevalence of PS and its association with adverse birth outcomes, found 22% of placentas to be infested using a maceration technique but only <1% using histologic examination. Additionally, no direct link to deleterious pregnancy outcomes could be shown.
CONCLUSIONS
PS is a highly unattended and underdiagnosed condition in endemic populations, due to a lack of awareness as well as low sensitivity of histopathological examinations. However, PS may play an important role in mediating or reinforcing adverse birth outcomes (ABO) such as fetal growth restriction (FGR) in maternal schistosomiasis, possibly by placental inflammation.
PubMed: 38921768
DOI: 10.3390/pathogens13060470 -
Pathogens (Basel, Switzerland) May 2024There is very little information available about transplacental infections by the papillomavirus in ruminants. However, recent evidence has emerged of the first report...
There is very little information available about transplacental infections by the papillomavirus in ruminants. However, recent evidence has emerged of the first report of vertical infections of bovine papillomavirus (BPV) in fetuses from naturally infected, pregnant cows. This study reports the coinfection of BPV and ovine papillomavirus (OaPV) in bovine fetuses from infected pregnant cows suffering from bladder tumors caused by simultaneous, persistent viral infections. Some molecular mechanisms involving the binary complex composed of Eras and platelet-derived growth factor β receptor (PDGFβR), by which BPVs and OaPVs contribute to reproductive disorders, have been investigated. A droplet digital polymerase chain reaction (ddPCR) was used to detect and quantify the nucleic acids of the BPVs of the genus (BPV1, BPV2, BPV13, and BPV14) and OaPVs belonging to the (OaPV1, OaPV2, and OaPV4) and (OaPV3) genera in the placenta and fetal organs (heart, lung, liver, and kidneys) of four bovine fetuses from four pregnant cows with neoplasia of the urinary bladder. A papillomaviral evaluation was also performed on the bladder tumors and peripheral blood of these pregnant cows. In all fetal and maternal samples, the genotype distribution of BPVs and OaPVs were evaluated using both their DNA and RNA. A BPV and OaPV coinfection was seen in bladder tumors, whereas only BPV infection was found in peripheral blood. The genotype distribution of both the BPVs and OaPVs detected in placentas and fetal organs indicated a stronger concordance with the viral genotypes detected in bladder tumors rather than in peripheral blood. This suggests that the viruses found in placentas and fetuses may have originated from infected bladders. Our study highlights the likelihood of vertical infections with BPVs and OaPVs and emphasizes the importance of gaining further insights into the mechanisms and consequences of this exposure. This study warrants further research as adverse pregnancy outcomes are a major source of economic losses in cattle breeding.
PubMed: 38921751
DOI: 10.3390/pathogens13060453 -
Current Issues in Molecular Biology Jun 2024When postmenopausal women are under stress conditions, this exacerbates mood disorders and issues with neuroimmune systems. The porcine placenta is known to relieve...
When postmenopausal women are under stress conditions, this exacerbates mood disorders and issues with neuroimmune systems. The porcine placenta is known to relieve menopausal depression in clinical trials, but its underlying mechanisms for depression and anti-inflammatory functions remain poorly defined. The present study was designed to examine the anti-inflammatory effects of enzymatic porcine placenta hydrolysate (EPPH) on LPS-induced levels of nitric oxide (NO), prostaglandin E2 (PGE2), corticosterone (CORT), and pro-inflammatory cytokine interleukin-1 beta (IL-1β) in RAW 264.7 macrophage cells. In addition, the neurite outgrowth of PC12 cells was evaluated to examine the effects of EPPH on neurite growth. To mimic the symptoms of women with menopause-related depression, a stressed ovariectomized (OVX) female mouse model was used to evaluate the antidepressant effects of EPPH. The female mice were randomly divided into five groups: (1) the sham-operated (Sham) group, (2) the OVX + repeated stress + saline-treated (OVX + ST) group, (3) the OVX + repeated stress + estradiol (0.2 mg/kg)-treated (positive control) group, (4) the OVX + repeated stress + EPPH (300 mg/kg)-treated (300) group, and (5) the OVX + repeated stress + EPPH (1500 mg/kg)-treated (1500) group. Female mice were OVX and repeatedly immobilization-stressed for 2 weeks (2 h/day). A tail suspension test was conducted on the 13th day, followed by the forced swimming test on the 14th day to assess the antidepressant effects of EPPH. After the behavioral tests, the levels of CORT, PGE2, and IL-1β were evaluated. In addition, c-Fos expression in the paraventricular nucleus (PVN) was evaluated using immunohistochemistry. The concentrations of NO, PGE2, and IL-1β stimulated by LPS were significantly reduced via the addition of EPPH to RAW 264.7 cells. EPPH significantly promoted neurite outgrowth in PC12 cells compared to that of the controls. In the tail suspension test, the duration of immobility was reduced in mice treated with EPPH 1500 compared to the OVX + ST group. The EPPH 1500 group had significantly decreased levels of c-Fos-positive neurons in the PVN and reduced levels of CORT and IL-1β in the serum of the Sham group. These results suggested that the high dose of EPPH administration induced the antidepressant-like effect in the ovariectomized mice with repeated stress via downregulating the levels of CORT, IL-1β, and PGE2 in the serum through reducing the expression of c-Fos in the PVN regions.
PubMed: 38921037
DOI: 10.3390/cimb46060366 -
Current Issues in Molecular Biology May 2024The expression and function of podoplanin (PDPN) in the normal human placenta has been debated in placental evaluation. This study emphasizes the importance of a...
Combining RNAscope, Immunohistochemistry (IHC) and Digital Image Analysis to Assess Podoplanin (PDPN) Protein and PDPN_mRNA Expression on Formalin-Fixed Paraffin-Embedded Normal Human Placenta Tissues.
The expression and function of podoplanin (PDPN) in the normal human placenta has been debated in placental evaluation. This study emphasizes the importance of a multimodal approach of PDPN expression in normal human placentas. A complete examination is performed using immunohistochemistry, RNAscope and automated Digital Image examination (DIA) interpretation. QuPath DIA-based analysis automatically generated the stromal and histological scores of PDPN expression for immunohistochemistry and RNAscope stains. The umbilical cord's isolated fibroblasts and luminal structures expressed PDPN protein and PDPN_mRNA. RNAscope detected PDPN_mRNA upregulation in syncytial placental knots trophoblastic cells, but immunohistochemistry did not certify this at the protein level. The study found a significant correlation between the IHC and RNAscope H-Score ( = 0.033) and Allred Score ( = 0.05). A successful multimodal strategy for PDPN assessment in human placentas confirmed PDPN expression heterogeneity in the full-term human normal placenta and umbilical cord at the protein and mRNA level. In placental syncytial knots trophoblastic cells, PDPN showed mRNA overexpression, suggesting a potential role in placenta maturation.
PubMed: 38920982
DOI: 10.3390/cimb46060310 -
Cells Jun 2024Mesenchymal stem cells (MSCs) of placental origin hold great promise in tissue engineering and regenerative medicine for diseases affecting cartilage and bone. However,...
Mesenchymal stem cells (MSCs) of placental origin hold great promise in tissue engineering and regenerative medicine for diseases affecting cartilage and bone. However, their utility has been limited by their tendency to undergo premature senescence and phenotypic drift into adipocytes. This study aimed to explore the potential involvement of a specific subset of aging and antiaging genes by measuring their expression prior to and following in vitro-induced differentiation of placental MSCs into chondrocytes and osteoblasts as opposed to adipocytes. The targeted genes of interest included the various transcript variants (lamin A, lamin C, and lamin A∆10), sirtuin 7 (SIRT7), and SM22α, along with the classic aging markers plasminogen activator inhibitor 1 (PAI-1), p53, and p16. MSCs were isolated from the decidua basalis of human term placentas, expanded, and then analyzed for phenotypic properties by flow cytometry and evaluated for colony-forming efficiency. The cells were then induced to differentiate in vitro into chondrocytes, osteocytes, and adipocytes following established protocols. The mRNA expression of the targeted genes was measured by RT-qPCR in the undifferentiated cells and those fully differentiated into the three cellular lineages. Compared to undifferentiated cells, the differentiated chondrocytes demonstrated decreased expression of SIRT7, along with decreased PAI-1, lamin A, and SM22α expression, but the expression of p16 and p53 increased, suggesting their tendency to undergo premature senescence. Interestingly, the cells maintained the expression of lamin C, which indicates that it is the primary lamin variant influencing the mechanoelastic properties of the differentiated cells. Notably, the expression of all targeted genes did not differ from the undifferentiated cells following osteogenic differentiation. On the other hand, the differentiation of the cells into adipocytes was associated with decreased expression of lamin A and PAI-1. The distinct patterns of expression of aging and antiaging genes following in vitro-induced differentiation of MSCs into chondrocytes, osteocytes, and adipocytes potentially reflect specific roles for these genes during and following differentiation in the fully functional cells. Understanding these roles and the network of signaling molecules involved can open opportunities to improve the handling and utility of MSCs as cellular precursors for the treatment of cartilage and bone diseases.
Topics: Humans; Mesenchymal Stem Cells; Female; Placenta; Cell Differentiation; Chondrogenesis; Pregnancy; Osteogenesis; Biomarkers; Cellular Senescence; Chondrocytes; Aging; Lamin Type A
PubMed: 38920652
DOI: 10.3390/cells13121022