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Journal of Diabetes and Metabolic... Dec 2023Gestational diabetes mellitus (GDM) is a pathological condition in which the placenta releases a hormone called human placental lactogen that prevents maternal insulin... (Review)
Review
UNLABELLED
Gestational diabetes mellitus (GDM) is a pathological condition in which the placenta releases a hormone called human placental lactogen that prevents maternal insulin uptake. GDM is characterised by varying degrees of carbohydrate intolerance and is first identified during pregnancy. Around 5-17% of pregnancies are GDM pregnancies. Older or obese women have a higher risk of developing GDM during gestation. Hyperglycemia is a classic manifestation of GDM and leads to alterations in eNOS and iNOS expression and subsequently causes ROS and RNS overproduction. ROS and RNS play an important role in maintaining normal physiology, when present in low concentrations. Increased concentrations of ROS is harmful and can cause cellular and tissue damage. Oxidative stress is defined as an imbalance between pro-oxidant and antioxidant molecules that manifests due to hyperglycemia. miRNAs are short, non-coding RNAs that play a critical role in regulating gene expression. Studies have shown that the placenta expresses more than 500 miRNAs, which play a crucial role in trophoblast division, movement, and apoptosis. Latest research has revealed that hyperglycemic conditions and increased oxidative stress, characteristic of GDM, can lead to the dysregulation of miRNAs. The placenta also releases miRNAs into the maternal circulation. The secreted miRNAs are encapsulated in exosomes or vesicles. These exosomes interact with tissues and organs at distant sites, releasing their cargo intracellularly. This crosstalk between hyperglycemia, ROS and miRNA expression in GDM has detrimental effects on both foetal and maternal health. One of the complications of GDM is preterm labour. GDM induced iNOS expression has been implicated in cervical ripening, which in turn causes preterm birth. This article focuses on the speculations of oxidative and nitrative stress markers that lead to detrimental effects in GDM. We have also envisaged the role of non-coding miRNA interactions in regulating gene expression for oxidative damage.
GRAPHICAL ABSTRACT
. I)(A) Placenta as a metabolic organ that provides the foetus with nutrients, oxygen and hormones to maintain pregnancy. Human placental lactogen (hPL) is one such hormone that is released into maternal circulation. hPL is known to induce insulin resistance. (B) ß-cell dysfunction leads to reduced glucose sensing and insulin production. Insulin resistance, a characteristic of GDM, exacerbates insulin ß cell dysfunction leading to maternal hyperglycemia. Hyperglycemia leads to increased ROS and RNS production through several mechanisms. Consequently, GDM is characterised by increased oxidative and nitrative stress.II)Exposure to maternal hyperglycemia causes increased ROS and RNS production in trophoblast cells. Oxidative stress caused by hyperglycemia may lead to eNOS uncoupling, causing eNOS to behave as a superoxide producing enzyme. iNOS expression in trophoblast cells leads to increased NO production. iNOS-derived NO reacts with ROS to produce RNS, thereby increasing nitrosative stress. Expression of antioxidant defences are reduced. Hyperglycemia and oxidative stress may alter the expression of some miRNAs. Some miRNAs are upregulated while others are downregulated. Some miRNAs are secreted into maternal circulation in the form of exosomes. Oxidative stress markers, nitrative stress markers and circulating miRNAs are found to be increased in maternal circulation.
PubMed: 37975145
DOI: 10.1007/s40200-023-01232-2 -
Cureus May 2023Mature cystic teratoma (MCT) is a benign germ cell tumor, histologically comprising components derived from mesoderm, ectoderm, and endoderm layer tissue. MCT usually...
Mature cystic teratoma (MCT) is a benign germ cell tumor, histologically comprising components derived from mesoderm, ectoderm, and endoderm layer tissue. MCT usually has foci of intestinal components and colonic epithelia. Pituitary teratomas containing complete colon features are very rare. Here, we present three cases of sellar teratoma in two men aged 50 and 65 years and a woman aged 30 years. All patients presented with asthenia, adynamia, and loss of strength. A pituitary mass was incidentally observed on magnetic resonance imaging. Histological features showed a mature teratoma formed by gut and colonic epithelium, extended lymphoid tissue with the formation of Peyer's patches, and muscular layer vestiges with a fibrous capsule. The immunohistochemical panel showed reactivity to cytokeratin (CK)7, CKAE6/AE7, carcinoembryonic antigen, octamer-binding transcription factor 4, cluster of differentiation (CD)20, CD3, vimentin, muscle actin, and in isolated cells. However, alpha-fetoprotein, beta-human chorionic gonadotropin, human placental lactogen, CK20, tumor suppressor protein 53, and Kirsten rat sarcoma were negative. This article describes the clinical and histological features of rare sellar masses as well as survival after therapy.
PubMed: 37292527
DOI: 10.7759/cureus.38729 -
Molecular Metabolism Jun 2017Hyperglycemia and systemic inflammation, hallmarks of Type 2 Diabetes (T2D), can induce the production of the inflammatory signaling molecule Prostaglandin E (PGE) in...
OBJECTIVE
Hyperglycemia and systemic inflammation, hallmarks of Type 2 Diabetes (T2D), can induce the production of the inflammatory signaling molecule Prostaglandin E (PGE) in islets. The effects of PGE are mediated by its four receptors, E-Prostanoid Receptors 1-4 (EP1-4). EP3 and EP4 play opposing roles in many cell types due to signaling through different G proteins, G and G, respectively. We previously found that EP3 and EP4 expression are reciprocally regulated by activation of the FoxM1 transcription factor, which promotes β-cell proliferation and survival. Our goal was to determine if EP3 and EP4 regulate β-cell proliferation and survival and, if so, to elucidate the downstream signaling mechanisms.
METHODS
β-cell proliferation was assessed in mouse and human islets treated with selective agonists and antagonists for EP3 (sulprostone and DG-041, respectively) and EP4 (CAY10598 and L-161,982, respectively). β-cell survival was measured in mouse and human islets treated with the EP3- and EP4-selective ligands in conjunction with a cytokine cocktail to induce cell death. Changes in gene expression and protein phosphorylation were analyzed in response to modulation of EP3 and EP4 activity in mouse islets.
RESULTS
Blockade of EP3 enhanced β-cell proliferation in young, but not old, mouse islets in part through phospholipase C (PLC)-γ1 activity. Blocking EP3 also increased human β-cell proliferation. EP4 modulation had no effect on proliferation alone. However, blockade of EP3 in combination with activation of EP4 enhanced human, but not mouse, β-cell proliferation. In both mouse and human islets, EP3 blockade or EP4 activation enhanced β-cell survival in the presence of cytokines. EP4 acts in a protein kinase A (PKA)-dependent manner to increase mouse β-cell survival. In addition, the positive effects of FoxM1 activation on β-cell survival are inhibited by EP3 and dependent on EP4 signaling.
CONCLUSIONS
Our results identify EP3 and EP4 as novel regulators of β-cell proliferation and survival in mouse and human islets .
Topics: Acrylamides; Animals; Cell Proliferation; Cell Survival; Cells, Cultured; Dinoprostone; Humans; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Phospholipase C gamma; Protein Kinase C; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Sulfones
PubMed: 28580285
DOI: 10.1016/j.molmet.2017.04.002 -
Frontiers in Microbiology 2021(), the etiological agent of Chagas Disease (CD), is transmitted to humans by infected kissing bugs, blood transfusion, organ transplantation, and from mother-to-child....
(), the etiological agent of Chagas Disease (CD), is transmitted to humans by infected kissing bugs, blood transfusion, organ transplantation, and from mother-to-child. Congenital transmission is now considered an important route of CD spread in non-endemic countries where no routine testing of pregnant women for the disease is implemented. The main cellular mechanisms that lead to fetal infection by , despite the presence of a placental barrier, remain unclear. Mother-to-child transmission most likely occurs when bloodstream trypomastigotes reach the placental intervillous space and interact with the large cellular surface provided by the syncytioptrophoblasts. These highly specialized cells not only function as a physical obstacle between mother and fetus, but also modulate immune responses against pathogen infections. To overcome the limitations associated with the use of human fetal tissues, we employed a three-dimensional (3D) cell culture model to recreate the human placenta environment. In this system, the trophoblast-derived JEG-3 cell line is co-cultured with human brain microvascular endothelial cells attached to microcarrier beads in a rotating bioreactor. Here, we report that 3D culture of JEG-3/HBMEC spheroids promote JEG-3 cells differentiation revealed by the formation of syncytia and production of β human chorionic gonadotropin and human placental lactogen (hPL). Under these growth conditions, we demonstrate that 3D-grown JEG-3 cells have reduced susceptibility to infection compared to JEG-3 cells grown in conventional tissue culture flasks. We also show that 3D-cultured JEG-3 cells release paracrine factors in the supernatant that prevent infection of non-trophoblastic cell lines. Our model of vertical transmission may help better understand the molecular processes by which parasites bypass the human placental barrier and could be exploited to evaluate therapeutics to reduce congenital CD.
PubMed: 33746919
DOI: 10.3389/fmicb.2021.626370 -
Modern Pathology : An Official Journal... Jan 2023Gestational trophoblastic diseases derived from the chorionic-type intermediate trophoblast include benign placental site nodule (PSN) and malignant epithelioid...
Molecular Analyses of Chorionic-Type Intermediate Trophoblastic Lesions: Atypical Placental Site Nodules are Closer to Placental Site Nodules Than Epithelioid Trophoblastic Tumors.
Gestational trophoblastic diseases derived from the chorionic-type intermediate trophoblast include benign placental site nodule (PSN) and malignant epithelioid trophoblastic tumor (ETT). Among PSNs, the World Health Organization classification introduced a new entity named atypical placental site nodule (APSN), corresponding to an ETT precursor, for which diagnostic criteria remain unclear, leading to a risk of overdiagnosis and difficulties in patient management. We retrospectively studied 8 PSNs, 7 APSNs, and 8 ETTs to better characterize this new entity and performed immunohistochemical analysis (p63, human placental lactogen, Cyclin E, and Ki67), transcriptional analysis using the NanoString method to quantify the expression of 760 genes involved in the main tumorigenesis pathways, and RNA sequencing to identify fusion transcripts. The immunohistochemical analysis did not reveal any significant difference in Cyclin E expression among the 3 groups (P = .476), whereas the Ki67 index was significantly (P < .001) higher in ETT samples than in APSN and PSN samples. None of the APSN samples harbored the LPCAT1::TERT fusion transcripts, in contrast to 1 of 6 ETT samples, as previously described in 2 of 3 ETT samples. The transcriptomic analysis allowed robust clustering of ETTs distinct from the APSN/PSN group but failed to differentiate APSNs from PSNs. Indeed, only 7 genes were differentially expressed between PSN and APSN samples; CCL19 upregulation and EPCAM downregulation were the most distinguishing features of APSNs. In contrast, 80 genes differentiated ETTs from APSNs, establishing a molecular signature for ETT. Gene set analysis identified significant enrichments in the DNA damage repair, immortality and stemness, and cell cycle signaling pathways when comparing ETTs and APSNs. These results suggested that APSN might not represent a distinct entity but rather a transitional stage between PSN and ETT. RNA sequencing and the transcriptional signature of ETT described herein could serve as triage for APSN from curettage or biopsy material, enabling the identification of cases that need further clinical investigations.
Topics: Female; Humans; Pregnancy; Trophoblastic Tumor, Placental Site; Cyclin E; Placenta; Ki-67 Antigen; Retrospective Studies; Uterine Neoplasms; Gestational Trophoblastic Disease
PubMed: 36788063
DOI: 10.1016/j.modpat.2022.100046 -
BioMed Research International 2016The primary sheep trophoblast cells (STCs) have a finite lifespan in culture. This feature limits the scope for long-term in vitro studies with STCs. This study was an...
The primary sheep trophoblast cells (STCs) have a finite lifespan in culture. This feature limits the scope for long-term in vitro studies with STCs. This study was an attempt to establish and characterize a telomerase-immortalized sheep trophoblast cell line. STCs were isolated and purified by using Percoll and specific immunoaffinity purification, respectively. The purified STCs were transfected with a plasmid carrying sequences of human telomerase reverse transcriptase (hTERT) to create immortalized sheep trophoblast cell line (hTERT-STCs). hTERT-STCs showed a stable expression of hTERT gene, serially passaged for a year, and showed active proliferation without signs of senescence. Cytokeratin 7 (CK-7), secreted human chorionic gonadotrophin subunit β (CG-β), placental lactogen (PL), and endogenous jaagsiekte sheep retrovirus (enJSRV) envelope genes were expressed in hTERT-STCs. Transwell cell invasion assay indicated that hTERT-STCs still possessed the same invasive characteristics as normal primary sheep trophoblast cells. hTERT-STCs could not grow in soft agar and did not develop into tumors in nude mice. In this study, we established a strain of immortalized sheep trophoblast cell line which could be gainfully employed in the future as an experimental model to study trophoblast cells with secretory function, invasive features, and probable biological function of enJSRV envelope genes.
Topics: Animals; Cell Line, Transformed; Gene Expression; Humans; Sheep; Telomerase; Trophoblasts
PubMed: 26998488
DOI: 10.1155/2016/5808575 -
The Journal of Reproduction and... Feb 2023In mice and humans, Nik-related protein kinase (Nrk) is an X-linked gene that encodes a serine/threonine kinase belonging to GCK group 4. Nrk knockout (Nrk KO) mice...
In mice and humans, Nik-related protein kinase (Nrk) is an X-linked gene that encodes a serine/threonine kinase belonging to GCK group 4. Nrk knockout (Nrk KO) mice exhibit delayed delivery, possibly due to defective communication between the Nrk KO conceptus and its mother. However, the mechanism of delayed labor remains largely unknown. Here, we found that in pregnant mothers with the Nrk KO conceptus, the serum progesterone (P4) and placental lactogen (PL-2) concentrations in late pregnancy were higher than those in the wild type. Moreover, we demonstrated that Nrk is expressed in trophoblast giant cells (TGCs) and syncytiotrophoblast-2 (SynT-2) in the labyrinth layer of the mouse placenta. In the human placenta, NRK is also expressed in Syn-T in villi. Both human Syn-T and mouse TGCs of the labyrinth layer are present within fetal tissues that are in direct contact with the maternal blood. The labyrinth layer of the Nrk KO conceptus was gigantic, with enlarged cytoplasm and Golgi bodies in the TGCs. To investigate the function of Nrk in the labyrinth layer, a differentially expressed gene (DEG) analysis was performed. The DEG analysis revealed that labor-promoting factors, such as prostaglandins, were decreased, and pregnancy-maintaining factors, such as the prolactin family and P4 receptor, were increased. These findings suggest that the Nrk KO mice exhibit delayed delivery owing to high P4 concentrations caused by the hypersecretion of pregnancy-maintaining factors, such as PL-2, from the placenta.
Topics: Humans; Pregnancy; Mice; Female; Animals; Placenta; Protein Serine-Threonine Kinases; Trophoblasts; Mice, Knockout; Prolactin
PubMed: 36567126
DOI: 10.1262/jrd.2022-120 -
International Journal of Molecular... Apr 2016Inadequate trophoblast invasion and increased trophoblast apoptosis cause serious pregnancy complications. Pleckstrin homology-like domain, family Α, member 2 (PHLDA2)...
Inadequate trophoblast invasion and increased trophoblast apoptosis cause serious pregnancy complications. Pleckstrin homology-like domain, family Α, member 2 (PHLDA2) has been linked to fetal size at birth and growth restriction in a number of studies. However, the impact of PHLDA2 on trophoblast function had not been studied previously, to the best of our knowledge. In the present study, immunofluorescence staining demonstrated that primary trophoblasts isolated from placental villous tissues were positive for cytokeratin 18 (CK18), vimentin and human placental lactogen (hPL). JEG-3 cells and primary trophoblasts were infected with lentivirus overexpressing PHLDA2. RT-qPCR and western blot analysis detected high levels of PHLDA2. A Cell Counting Kit-8 (CCK-8) assay showed that PHLDA2 overexpression inhibited trophoblast proliferation. In addition, PHLDA2 significantly induced apoptosis, as evidenced by Annexin V-FITC/propidium iodide (PI) and Hoechst staining, along with activation of Bax and caspase-3 and also decreased Bcl-2 expression. Further investigation showed that PHLDA2 effectively induced reactive oxygen species (ROS) generation, caused cytochrome c release from the mitochondria into the cytosol and decreased mitochondrial membrane potential. PHLDA2 likely induced apoptosis through the mitochondrial pathway. Wound healing and Transwell assays indicated that PHLDA2 overexpression efficiently suppressed cell migration and invasion. These data suggest that PHLDA2 plays an important role in the occurrence and development of pregnancy complications by promoting trophoblast apoptosis and suppressing cell invasion.
Topics: Apoptosis; Cell Line; Cell Movement; Cell Proliferation; Cells, Cultured; Female; Humans; Lentivirus; Membrane Potential, Mitochondrial; Nuclear Proteins; Pregnancy; Pregnancy Complications; Reactive Oxygen Species; Trophoblasts; Up-Regulation
PubMed: 26935516
DOI: 10.3892/ijmm.2016.2508 -
Journal of Physiology and Pharmacology... Dec 2019Apelin was thought to be an adipocyte-specific hormone, but recent studies have indicated a link between apelin and placenta function e.g. cell proliferation. The aim of...
Apelin decreased placental hormone secretion by human trophoblast BeWo cells via apelin receptor, protein kinase A and extracellular signal-regulated kinases 1/2 activation.
Apelin was thought to be an adipocyte-specific hormone, but recent studies have indicated a link between apelin and placenta function e.g. cell proliferation. The aim of the study was investigating dose- and time-dependent effect of apelin on hormone secretion including steroids: progesterone (P4) and estradiol (E2) and proteins: chorionic gonadotropin (hCG), human placental lactogen (hPL), placental growth factor (PLGF), as well as protein expression of steroid enzymes (3βHSD, CYP19) and protein hormones (hCG, hPL and PLGF) in placental cells. Syncytiotrophoblast BeWo cells, as human trophoblast models, were treated for 24, 48, and 72 hours with the human recombinant apelin at doses 0.02, 0.2, 2.0, 20 and 200 ng/ml followed by culture medium. Concentrations of the above hormones were studied by ELISA kits. Furthermore, protein expression of steroid enzymes and protein hormones were measured using Western blot. Our results showed that apelin significantly decreased both steroid and protein hormones by inhibiting steroid enzymes or protein hormone expression. Moreover, we demonstrated that apelin at dose 2.0 ng/ml increased phosphorylation of protein kinase A (PKA) from 1 to 60 min of BeWo cell incubation. Inhibitory effect of apelin on P4, E2 and PLGF secretion were abolished when BeWo cells were cultured in the presence of ML221, an apelin receptor antagonist, PD98059, an extracellular signal-regulated kinases (ERK1/2) antagonist and KT5720, a PKA antagonist. In turn, secretion of hCG and hPL occurs only in the presence of ML221 and PD98059. In conclusion, our results indicate that apelin can be considered as a gestational hormone implied in the endocrine function of the human placenta, with an important role in controlling the production of steroid and protein hormones in placental BeWo cells.
Topics: Apelin; Apelin Receptors; Cell Line, Tumor; Choriocarcinoma; Chorionic Gonadotropin; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Female; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Placenta; Placenta Growth Factor; Placental Lactogen; Pregnancy; Time Factors; Trophoblasts
PubMed: 32084650
DOI: 10.26402/jpp.2019.6.08 -
Development (Cambridge, England) Dec 2014Sirh7/Ldoc1 [sushi-ichi retrotransposon homolog 7/leucine zipper, downregulated in cancer 1, also called mammalian retrotransposon-derived 7 (Mart7)] is one of the newly...
Sirh7/Ldoc1 [sushi-ichi retrotransposon homolog 7/leucine zipper, downregulated in cancer 1, also called mammalian retrotransposon-derived 7 (Mart7)] is one of the newly acquired genes from LTR retrotransposons in eutherian mammals. Interestingly, Sirh7/Ldoc1 knockout (KO) mice exhibited abnormal placental cell differentiation/maturation, leading to an overproduction of placental progesterone (P4) and placental lactogen 1 (PL1) from trophoblast giant cells (TGCs). The placenta is an organ that is essential for mammalian viviparity and plays a major endocrinological role during pregnancy in addition to providing nutrients and oxygen to the fetus. P4 is an essential hormone in the preparation and maintenance of pregnancy and the determination of the timing of parturition in mammals; however, the biological significance of placental P4 in rodents is not properly recognized. Here, we demonstrate that mouse placentas do produce P4 in mid-gestation, coincident with a temporal reduction in ovarian P4, suggesting that it plays a role in the protection of the conceptuses specifically in this period. Pregnant Sirh7/Ldoc1 knockout females also displayed delayed parturition associated with a low pup weaning rate. All these results suggest that Sirh7/Ldoc1 has undergone positive selection during eutherian evolution as a eutherian-specific acquired gene because it impacts reproductive fitness via the regulation of placental endocrine function.
Topics: Animals; DNA Primers; Female; Genotype; In Situ Hybridization; Mice; Mice, Knockout; Mifepristone; Parturition; Placenta; Placental Lactogen; Polymerase Chain Reaction; Pregnancy; Progesterone; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Time Factors
PubMed: 25468940
DOI: 10.1242/dev.114520