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IScience May 2020We evaluated the contribution of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a high-affinity carrier for prostaglandins (PGs), to the parturition...
We evaluated the contribution of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a high-affinity carrier for prostaglandins (PGs), to the parturition process. At gestational day (GD) 15.5, OATP2A1 is co-localized with 15-hydroxy-PG dehydrogenase in the mouse placental junctional zone and facilitates PG degradation by delivering PGs to the cytoplasm. Slco2a1 (+/-) females mated with Slco2a1 (-/-) males frequently showed elevated circulating progesterone at GD18.5 and delayed parturition. Progesterone receptor inhibition by RU486 treatment at GD18.5 blocked the delay of parturition. In the junctional zone, PGE stimulated placental lactogen II (PL-II) production, resulting in higher expression of PL-II in Slco2a1 (-/-) placenta at GD18.5. Indomethacin treatment at GD15.5 suppressed the PL-II overproduction at GD18.5 in Slco2a1 (-/-) embryo-bearing dams, which promoted progesterone withdrawal and corrected the delayed parturition. These results suggest that extracellular PGE reduction by OATP2A1 at mid-pregnancy would be associated with progesterone withdrawal by suppressing PL-II production, triggering parturition onset.
PubMed: 32408168
DOI: 10.1016/j.isci.2020.101098 -
Endocrine Journal May 2024The placenta secretes a prolactin (PRL)-like hormone PRL3B1 (placental lactogen II), a luteotropic hormone essential for maintaining pregnancy until labor in mice. A...
The placenta secretes a prolactin (PRL)-like hormone PRL3B1 (placental lactogen II), a luteotropic hormone essential for maintaining pregnancy until labor in mice. A report from 1984 examined the secretion pattern of PRL3B1 in prepartum mice. In the current study, we found contradictory findings in the secretion pattern that invalidate the previous report. By measuring maternal plasma PRL3B1 and PRL every 4 hrs from gestational day 17 (G17), we newly discovered that maternal plasma PRL3B1 levels decrease rapidly in prepartum C57BL/6 mice. Interestingly, the onset of this decline coincided with the PRL surge at G18, demonstrating a plasma prolactin axis shift from placental to pituitary origin. We also found that maternal plasma progesterone regression precedes the onset of the PRL shift. The level of Prl3b1 mRNA was determined by RT-qPCR in the placenta and remained stable until parturition, implying that PRL3B1 peptide production or secretion was suppressed. We hypothesized that production of the PRL family, the 25 paralogous PRL proteins exclusively expressed in mice placenta, would decrease alongside PRL3B1 during this period. To investigate this hypothesis and to seek proteomic changes, we performed a shotgun proteome analysis of the placental tissue using data-independent acquisition mass spectrometry (DIA-MS). Up to 5,891 proteins were identified, including 17 PRL family members. Relative quantitative analysis between embryonic day 17 (E17) and E18 placentas showed no significant difference in the expression of PRL3B1 and most PRL family members except PRL7C1. These results suggest that PRL3B1 secretion from the placenta is suppressed at G18 (E18).
PubMed: 38749736
DOI: 10.1507/endocrj.EJ23-0724 -
Diabetes Jul 2020Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells in vitro and in vivo...
Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells in vitro and in vivo against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway of endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines whether lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita (Ak) mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS-1 cells, primary rodent and human β-cells in vitro against two distinct ER stressors, tunicamycin and thapsigargin, through activation of the JAK2/STAT5 pathway. Lactogens mitigate expression of proapoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS-1 cells and rodent islets. Transgenic expression of placental lactogen in β-cells of Ak mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Ak littermates. These are the first studies in any cell type demonstrating that lactogens modulate the ER stress pathway, causing enhanced β-cell survival and reduced diabetes incidence in the face of chronic ER stress.
Topics: Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus; Endoplasmic Reticulum Stress; Female; Glucose; Humans; Insulin; Insulin-Secreting Cells; Janus Kinase 2; Male; Mice; Mice, Inbred C57BL; Placental Lactogen; Prolactin; STAT5 Transcription Factor; Signal Transduction
PubMed: 32332156
DOI: 10.2337/db19-0909 -
Iranian Journal of Radiology : a... Apr 2016Placental site trophoblastic tumor (PSTT) is a very rare variant of gestational trophoblastic tumor. It can occur after normal termination of pregnancy or spontaneous...
Placental site trophoblastic tumor (PSTT) is a very rare variant of gestational trophoblastic tumor. It can occur after normal termination of pregnancy or spontaneous abortion and ectopic or molar pregnancy. There is a wide range of clinical manifestations from a benign condition to an aggressive disease with fatal outcome. One of the most important characteristics of PSTT, unlike other forms of gestational trophoblastic diseases (GTD) is the presence of low beta-subunit of human chorionic gonadotropin (β-hCG) levels because it is a neoplastic proliferation of intermediate trophoblastic cells. However, human placental lactogen (hPL) is increased on histologic section and in the serum of patients too. We present a case of PSTT and discuss the differential diagnosis in order to further familiarize physicians with the diagnosis and treatment of this disease. It has a varied clinical spectrum and usually presents with irregular vaginal bleeding or amenorrhea. Diagnosis is confirmed by dilatation and curettage (D and C) and hysterectomy. Because chemotherapy is not effective, surgery is the cornerstone of treatment. This case is presented because it is a rare neoplasm with different treatments and it should be differentiated from molar pregnancy.
PubMed: 27679689
DOI: 10.5812/iranjradiol.18480 -
Implications for the offspring of circulating factors involved in beta cell adaptation in pregnancy.Acta Obstetricia Et Gynecologica... Nov 2014Several studies have shown an increase in beta cell mass during pregnancy. Somatolactogenic hormones are known to stimulate the proliferation of existing beta cells in...
OBJECTIVE
Several studies have shown an increase in beta cell mass during pregnancy. Somatolactogenic hormones are known to stimulate the proliferation of existing beta cells in rodents whereas the mechanism in humans is still unclear. We hypothesize that in addition to somatolactogenic hormones there are other circulating factors involved in beta cell adaptation to pregnancy. This study aimed at screening for potential pregnancy-associated circulating beta cell growth factors.
SAMPLES
Serum samples from nonpregnant and pregnant women.
METHODS
The effect of serum from pregnant women on the proliferation of rat beta cells was studied using [3H]thymidine incorporation and 5-ethynyl-2'-deoxyuridine proliferation assays. In addition, serum from pregnant and nonpregnant women was fractionated by gel filtration and high performance liquid chromatography. The fractionated serum was screened for mitogenic activity in INS-1E cells. Proteins and peptides in mitogenic active serum fractions were identified by amino acid sequencing and mass spectrometry.
MAIN OUTCOME MEASURES
Presence of circulating beta cell proliferating factors.
RESULTS
Late gestational pregnancy serum significantly increased proliferation of rat beta cells compared with early pregnancy and nonpregnancy. The mitogenic active serum fractions contained proteins and peptides derived from kininogen-1, fibrinogen-α, α1-antitrypsin, apolipoprotein-A1, placental lactogen, angiotensinogen and serum albumin.
CONCLUSION
Pregnancy serum is able to stimulate proliferation of rat beta cells. We have identified several circulating factors that may contribute to beta cell adaptation to pregnancy. Further studies are needed to elucidate their possible role in glucose homeostasis in the mother and her offspring.
Topics: Adaptation, Physiological; Adult; Amino Acid Sequence; Angiotensinogen; Animals; Animals, Newborn; Apolipoprotein A-I; Biomarkers; Cell Proliferation; Cells, Cultured; Chromatography, Gel; Chromatography, High Pressure Liquid; Female; Fibrinogen; Humans; Insulin-Secreting Cells; Kininogens; Mass Spectrometry; Placental Lactogen; Pregnancy; Pregnancy Trimesters; Rats; Rats, Wistar; Serum Albumin; alpha 1-Antitrypsin
PubMed: 25223212
DOI: 10.1111/aogs.12505 -
Diabetes Nov 2015Pregnancy in rodents is associated with a two- to threefold increase in β-cell mass, which is attributable to large increases in β-cell proliferation, complimented by...
Pregnancy in rodents is associated with a two- to threefold increase in β-cell mass, which is attributable to large increases in β-cell proliferation, complimented by increases in β-cell size, survival, and function and mediated mainly by the lactogenic hormones prolactin (PRL) and placental lactogens. In humans, however, β-cell mass does not increase as dramatically during pregnancy, and PRL fails to activate proliferation in human islets in vitro. To determine why, we explored the human PRL-prolactin receptor (hPRLR)-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5)-cyclin-cdk signaling cascade in human β-cells. Surprisingly, adult human β-cells express little or no PRLR. As expected, restoration of the hPRLR in human β-cells rescued JAK2-STAT5 signaling in response to PRL. However, rescuing hPRLR-STAT5 signaling nevertheless failed to confer proliferative ability on adult human β-cells in response to PRL. Surprisingly, mouse (but not human) Stat5a overexpression led to upregulation of cyclins D1-3 and cdk4, as well as their nuclear translocation, all of which are associated with β-cell cycle entry. Collectively, the findings show that human β-cells fail to proliferate in response to PRL for multiple reasons, one of which is a paucity of functional PRL receptors, and that murine Stat5 overexpression is able to bypass these impediments.
Topics: Animals; Cell Line; Cell Proliferation; Cyclin D; Cyclin-Dependent Kinase 4; Humans; Insulin-Secreting Cells; Mice; Phosphorylation; Prolactin; Receptors, Prolactin; STAT5 Transcription Factor; Signal Transduction; Up-Regulation
PubMed: 26159175
DOI: 10.2337/db15-0083 -
International Journal of Clinical and... 2014Epithelioid trophoblastic tumor (ETT) is a rare trophoblastic tumor originating from chorionic-type intermediate trophoblasts (ITs). It is usually associated with a... (Review)
Review
Epithelioid trophoblastic tumor (ETT) is a rare trophoblastic tumor originating from chorionic-type intermediate trophoblasts (ITs). It is usually associated with a prior gestational event. We present a 44-year-old woman who had unusual pregnancy related history. The patient received her second spontaneous abortion at the age of 25 years and had suffered from choriocarcinoma in left board ligament at the age of 29 years. She admitted no more treatment after 3 courses of multiagent chemotherapy when serum β-hCG returned to normal. Then she had Full-term delivery, induced abortion at the ages of 32, 33 years. The patient had high serum levels of beta-human chorionic gonadotropin (6587 IU/L). Microscopically, the tumor was composed of mainly mononuclear tumor cells, grew in cords, nests, and sheets within which were aggregates of hyaline material. Most were with distinct cell borders, eosinophilic cytoplasm. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (AE1/AE3, CK18), P63, focal reactivity for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The Ki-67 index was 77%. The histological and immunohistochemical features were characteristic of epithelioid trophoblastic tumor. This is the first reported case of these two gestational trophoblastic tumor happened on one person with the intervening normal pregnancy.
Topics: Abortion, Induced; Adult; Broad Ligament; Choriocarcinoma; Female; Humans; Neoplasms, Second Primary; Peritoneal Neoplasms; Pregnancy; Reproductive History; Trophoblastic Neoplasms; Uterine Neoplasms
PubMed: 25550880
DOI: No ID Found -
International Journal of Molecular... Oct 2017Diabetes mellitus (DM) is a multifactorial disease orphan of a cure. Regenerative medicine has been proposed as novel strategy for DM therapy. Human fibroblast growth...
Diabetes mellitus (DM) is a multifactorial disease orphan of a cure. Regenerative medicine has been proposed as novel strategy for DM therapy. Human fibroblast growth factor (FGF)-2b controls β-cell clusters via autocrine action, and human placental lactogen (hPL)-A increases functional β-cells. We hypothesized whether FGF-2b/hPL-A treatment induces β-cell differentiation from ductal/non-endocrine precursor(s) by modulating specific genes expression. Human pancreatic ductal-cells (PANC-1) and non-endocrine pancreatic cells were treated with FGF-2b plus hPL-A at 500 ng/mL. Cytofluorimetry and Immunofluorescence have been performed to detect expression of endocrine, ductal and acinar markers. Bromodeoxyuridine incorporation and annexin-V quantified cells proliferation and apoptosis. Insulin secretion was assessed by RIA kit, and electron microscopy analyzed islet-like clusters. Increase in PANC-1 duct cells de-differentiation into islet-like aggregates was observed after FGF-2b/hPL-A treatment showing ultrastructure typical of islets-aggregates. These clusters, after stimulation with FGF-2b/hPL-A, had significant ( < 0.05) increase in insulin, C-peptide, pancreatic and duodenal homeobox 1 (PDX-1), Nkx2.2, Nkx6.1, somatostatin, glucagon, and glucose transporter 2 (Glut-2), compared with control cells. Markers of PANC-1 (Cytokeratin-19, MUC-1, CA19-9) were decreased ( < 0.05). These aggregates after treatment with FGF-2b/hPL-A significantly reduced levels of apoptosis. FGF-2b and hPL-A are promising candidates for regenerative therapy in DM by inducing de-differentiation of stem cells modulating pivotal endocrine genes.
Topics: Cell Differentiation; Diabetes Mellitus; Female; Fibroblast Growth Factor 2; Homeobox Protein Nkx-2.2; Homeodomain Proteins; Humans; Insulin-Secreting Cells; Male; Middle Aged; Nuclear Proteins; Pancreatic Ducts; Placental Lactogen; Regenerative Medicine; Transcription Factors
PubMed: 29068419
DOI: 10.3390/ijms18112234 -
American Journal of Physiology.... Apr 2018The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression...
The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.
Topics: Adaptation, Physiological; Animals; Animals, Newborn; Cell Differentiation; Cells, Cultured; Diet, High-Fat; Gene Expression Regulation, Developmental; Glucose; Hepatocyte Nuclear Factor 6; Homeodomain Proteins; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Transgenic; Multipotent Stem Cells; Organogenesis; Trans-Activators
PubMed: 29351489
DOI: 10.1152/ajpendo.00260.2017 -
The Cochrane Database of Systematic... May 2019Stillbirth affects 2.6 million pregnancies worldwide each year. Whilst the majority of cases occur in low- and middle-income countries, stillbirth remains an important... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Stillbirth affects 2.6 million pregnancies worldwide each year. Whilst the majority of cases occur in low- and middle-income countries, stillbirth remains an important clinical issue for high-income countries (HICs) - with both the UK and the USA reporting rates above the mean for HICs. In HICs, the most frequently reported association with stillbirth is placental dysfunction. Placental dysfunction may be evident clinically as fetal growth restriction (FGR) and small-for-dates infants. It can be caused by placental abruption or hypertensive disorders of pregnancy and many other disorders and factorsPlacental abnormalities are noted in 11% to 65% of stillbirths. Identification of FGA is difficult in utero. Small-for-gestational age (SGA), as assessed after birth, is the most commonly used surrogate measure for this outcome. The degree of SGA is associated with the likelihood of FGR; 30% of infants with a birthweight < 10th centile are thought to be FGR, while 70% of infants with a birthweight < 3rd centile are thought to be FGR. Critically, SGA is the most significant antenatal risk factor for a stillborn infant. Correct identification of SGA infants is associated with a reduction in the perinatal mortality rate. However, currently used tests, such as measurement of symphysis-fundal height, have a low reported sensitivity and specificity for the identification of SGA infants.
OBJECTIVES
The primary objective was to assess and compare the diagnostic accuracy of ultrasound assessment of fetal growth by estimated fetal weight (EFW) and placental biomarkers alone and in any combination used after 24 weeks of pregnancy in the identification of placental dysfunction as evidenced by either stillbirth, or birth of a SGA infant. Secondary objectives were to investigate the effect of clinical and methodological factors on test performance.
SEARCH METHODS
We developed full search strategies with no language or date restrictions. The following sources were searched: MEDLINE, MEDLINE In Process and Embase via Ovid, Cochrane (Wiley) CENTRAL, Science Citation Index (Web of Science), CINAHL (EBSCO) with search strategies adapted for each database as required; ISRCTN Registry, UK Clinical Trials Gateway, WHO International Clinical Trials Portal and ClinicalTrials.gov for ongoing studies; specialist abstract and conference proceeding resources (British Library's ZETOC and Web of Science Conference Proceedings Citation Index). Search last conducted in Ocober 2016.
SELECTION CRITERIA
We included studies of pregnant women of any age with a gestation of at least 24 weeks if relevant outcomes of pregnancy (live birth/stillbirth; SGA infant) were assessed. Studies were included irrespective of whether pregnant women were deemed to be low or high risk for complications or were of mixed populations (low and high risk). Pregnancies complicated by fetal abnormalities and multi-fetal pregnancies were excluded as they have a higher risk of stillbirth from non-placental causes. With regard to biochemical tests, we included assays performed using any technique and at any threshold used to determine test positivity.
DATA COLLECTION AND ANALYSIS
We extracted the numbers of true positive, false positive, false negative, and true negative test results from each study. We assessed risk of bias and applicability using the QUADAS-2 tool. Meta-analyses were performed using the hierarchical summary ROC model to estimate and compare test accuracy.
MAIN RESULTS
We included 91 studies that evaluated seven tests - blood tests for human placental lactogen (hPL), oestriol, placental growth factor (PlGF) and uric acid, ultrasound EFW and placental grading and urinary oestriol - in a total of 175,426 pregnant women, in which 15,471 pregnancies ended in the birth of a small baby and 740 pregnancies which ended in stillbirth. The quality of included studies was variable with most domains at low risk of bias although 59% of studies were deemed to be of unclear risk of bias for the reference standard domain. Fifty-three per cent of studies were of high concern for applicability due to inclusion of only high- or low-risk women.Using all available data for SGA (86 studies; 159,490 pregnancies involving 15,471 SGA infants), there was evidence of a difference in accuracy (P < 0.0001) between the seven tests for detecting pregnancies that are SGA at birth. Ultrasound EFW was the most accurate test for detecting SGA at birth with a diagnostic odds ratio (DOR) of 21.3 (95% CI 13.1 to 34.6); hPL was the most accurate biochemical test with a DOR of 4.78 (95% CI 3.21 to 7.13). In a hypothetical cohort of 1000 pregnant women, at the median specificity of 0.88 and median prevalence of 19%, EFW, hPL, oestriol, urinary oestriol, uric acid, PlGF and placental grading will miss 50 (95% CI 32 to 68), 116 (97 to 133), 124 (108 to 137), 127 (95 to 152), 139 (118 to 154), 144 (118 to 161), and 144 (122 to 161) SGA infants, respectively. For the detection of pregnancies ending in stillbirth (21 studies; 100,687 pregnancies involving 740 stillbirths), in an indirect comparison of the four biochemical tests, PlGF was the most accurate test with a DOR of 49.2 (95% CI 12.7 to 191). In a hypothetical cohort of 1000 pregnant women, at the median specificity of 0.78 and median prevalence of 1.7%, PlGF, hPL, urinary oestriol and uric acid will miss 2 (95% CI 0 to 4), 4 (2 to 8), 6 (6 to 7) and 8 (3 to 13) stillbirths, respectively. No studies assessed the accuracy of ultrasound EFW for detection of pregnancy ending in stillbirth.
AUTHORS' CONCLUSIONS
Biochemical markers of placental dysfunction used alone have insufficient accuracy to identify pregnancies ending in SGA or stillbirth. Studies combining U and placental biomarkers are needed to determine whether this approach improves diagnostic accuracy over the use of ultrasound estimation of fetal size or biochemical markers of placental dysfunction used alone. Many of the studies included in this review were carried out between 1974 and 2016. Studies of placental substances were mostly carried out before 1991 and after 2013; earlier studies may not reflect developments in test technology.
Topics: Female; Fetal Development; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Perinatal Mortality; Placenta; Pregnancy; Pregnancy Outcome; Stillbirth; Ultrasonography, Prenatal
PubMed: 31087568
DOI: 10.1002/14651858.CD012245.pub2