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1.
J Clin Pharmacol ; 62 Suppl 1: 140-146, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36106779

RESUMO

Morphine may be administered in pregnant women as an analgesic agent. The transplacental pharmacokinetics (PK) of morphine varies during pregnancy because of physiological and metabolic changes. In this work, we use a multi-compartment model to simulate ex vivo human placental transfer studies of morphine. The computational model is based on a recently published model for metformin with both passive and active transport kinetics. Modifications were made to incorporate morphine-specific transfer parameters. Parameters for the PK models were determined via the nonlinear regression method. In addition, the Latin hypercube sampling (LHS) method was used for the global parameter analysis of the model. Simulation results show good agreement between the model and observed fetal and maternal morphine concentrations. In addition, the lower efflux of morphine from fetal to maternal plasma reflects reduced P-glycoprotein (P-gp) transport as pregnancy progresses, which leads to slower clearance of morphine in the maternal plasma. The LHS analysis also indicates the more significant roles played by the passive diffusion parameters than the active transport parameter on the fetal/maternal morphine concentrations. In conclusion, we used an in silico model to investigate the transplacental properties of morphine and to predict the in vivo transplacental properties of morphine when PK parameters change.


Assuntos
Troca Materno-Fetal , Morfina , Simulação por Computador , Feminino , Humanos , Troca Materno-Fetal/fisiologia , Modelos Biológicos , Placenta/metabolismo , Gravidez
2.
J Clin Pharmacol ; 62 Suppl 1: S115-S128, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36106784

RESUMO

There is limited information about the transfer of antidepressants and antipsychotics across the human placenta. The objective of the current review was to systematically screen the scientific literature using relevant keywords to collect quantitative data on placental transfer of these drugs in humans and to give an overview of current modeling approaches used in this context. The collected data encompassed clinically measured fetal:maternal (F:M) concentration ratios (ie, the ratio between drug concentrations measured in the umbilical cord and drug concentrations measured in the mother) and transfer data obtained from ex vivo cotyledon perfusion experiments. These data were found for 18 antidepressants and some of their pharmacologically active metabolites, and for 10 antipsychotics and the metabolites thereof. Based on the collected data, similar maternal and fetal exposure could be observed for only a few compounds (eg, norfluoxetine and desvenlafaxine), whereas for most drugs (eg, paroxetine, sertraline, and quetiapine), fetal exposure appeared to be on average lower than maternal exposure. Venlafaxine appeared to be an exception in that the data indicated equivalent or higher concentrations in the umbilical cord than in the mother. Physiologically based pharmacokinetic (PBPK) models were sporadically used to investigate maternal pharmacokinetics of antidepressants or antipsychotics (eg, for sertraline, aripiprazole, and olanzapine), although without explicitly addressing fetal drug exposure. It is recommended that PBPK modeling is applied more frequently to these drugs. Although no substitute for clinical studies, these tools can help to better understand pregnancy-induced pharmacokinetic changes and ultimately contribute to a more evidence-based pharmacotherapy of depression and psychosis in pregnant subjects.


Assuntos
Antipsicóticos , Placenta , Antidepressivos , Antipsicóticos/uso terapêutico , Feminino , Humanos , Troca Materno-Fetal/fisiologia , Placenta/metabolismo , Gravidez , Sertralina/metabolismo
3.
Environ Health Perspect ; 130(9): 97006, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36129437

RESUMO

BACKGROUND: The first evidence of micro- and nanoplastic (MNP) exposure in the human placenta is emerging. However, the toxicokinetics and toxicity of MNPs in the placenta, specifically environmentally relevant particles, remain unclear. OBJECTIVES: We examined the transport, uptake, and toxicity of pristine and experimentally weathered MNPs in nonsyncytialized and syncytialized BeWo b30 choriocarcinoma cells. METHODS: We performed untargeted chemical characterization of pristine and weathered MNPs using liquid chromatography high-resolution mass spectrometry to evaluate compositional differences following particle weathering. We investigated cellular internalization of pristine and weathered polystyrene (PS; 0.05-10µm) and high-density polyethylene (HDPE; 0-80µm) particles using high-resolution confocal imaging and three-dimensional rendering. We investigated the influence of particle coating with human plasma on the cellular transport of PS particles using a transwell setup and examined the influence of acute MNP exposure on cell viability, damage to the plasma membrane, and expression of genes involved in steroidogenesis. RESULTS: Chemical characterization of MNPs showed a significantly higher number of unique features in pristine particles in comparison with weathered particles. Size-dependent placental uptake of pristine and weathered MNPs was observed in both placental cell types after 24 h exposure. Cellular transport was limited and size-dependent and was not influenced by particle coating with human plasma. None of the MNPs affected cell viability. Damage to the plasma membrane was observed only for 0.05µm PS particles in the nonsyncytialized cells at the highest concentration tested (100µg/mL). Modest down-regulation of hsd17b1 was observed in syncytialized cells exposed to pristine MNPs. DISCUSSION: Our results suggest that pristine and weathered MNPs are internalized and translocated in placental cells in vitro. Effects on gene expression observed upon pristine PS and HDPE particle exposure warrant further examination. More in-depth investigations are needed to better understand the potential health risks of MNP and chemicals associated with them under environmentally relevant exposure scenarios. https://doi.org/10.1289/EHP10873.


Assuntos
Microplásticos , Poliestirenos , Sobrevivência Celular , Feminino , Humanos , Placenta/metabolismo , Polietileno/metabolismo , Polietileno/farmacologia , Gravidez
4.
PLoS One ; 17(9): e0274762, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36129958

RESUMO

Pregnancy in Sickle Cell Disease (SCD) women is associated to increased risk of clinical and obstetrical complications. Placentas from SCD pregnancies can present increased abnormal findings, which may lead to placental insufficiency, favoring adverse perinatal outcome. These placental abnormalities are well known and reported, however little is known about the molecular mechanisms, such as epigenetics. Thus, our aim was to evaluate the DNA methylation profile in placentas from women with SCD (HbSS and HbSC genotypes), compared to uncomplicated controls (HbAA). We included in this study 11 pregnant women with HbSS, 11 with HbSC and 21 with HbAA genotypes. Illumina Methylation EPIC BeadChip was used to assess the whole placental DNA methylation. Pyrosequencing was used for array data validation and qRT-PCR was applied for gene expression analysis. Our results showed high frequency of hypermethylated CpGs sites in HbSS and HbSC groups with 73.5% and 76.2% respectively, when compared with the control group. Differentially methylated regions (DMRs) also showed an increased hypermethylation status for the HbSS (89%) and HbSC (86%) groups, when compared with the control group methylation data. DMRs were selected for methylation validation (4 DMRs-HbSS and 3 DMRs the HbSC groups) and after analyses three were validated in the HbSS group, and none in the HbSC group. The gene expression analysis showed differential expression for the PTGFR (-2.97-fold) and GPR56 (3.0-fold) genes in the HbSS group, and for the SPOCK1 (-2.40-fold) and ADCY4 (1.80-fold) genes in the HbSC group. Taken together, these data strongly suggest that SCD (HbSS and HbSC genotypes) can alter placental DNA methylation and lead to gene expression changes. These changes possibly contribute to abnormal placental development and could impact in the clinical course, especially for the fetus, possibly leading to increased risk of abortion, fetal growth restriction (FGR), stillbirth, small for gestational age newborns and prematurity.


Assuntos
Anemia Falciforme , Doença da Hemoglobina SC , Anemia Falciforme/complicações , Anemia Falciforme/genética , Epigênese Genética , Feminino , Doença da Hemoglobina SC/genética , Hemoglobina Falciforme/genética , Humanos , Recém-Nascido , Placenta/metabolismo , Gravidez , Proteoglicanas/metabolismo
5.
J Clin Pharmacol ; 62 Suppl 1: S94-S114, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36106781

RESUMO

Medication (drug) use in human pregnancy is prevalent. Determining fetal safety and efficacy of drugs is logistically challenging. However, predicting (not measuring) fetal drug exposure (systemic and tissue) throughout pregnancy is possible through maternal-fetal physiologically based pharmacokinetic (PBPK) modeling and simulation. Such prediction can inform fetal drug safety and efficacy. Fetal drug exposure can be quantified in 2 complementary ways. First, the ratio of the steady-state unbound plasma concentration in the fetal plasma (or area under the plasma concentration-time curve) to the corresponding maternal plasma concentration (ie, Kp,uu ). Second, the maximum unbound peak (Cu,max,ss,f ) and trough (Cu,min,ss,f ) fetal steady-state plasma concentrations. We (and others) have developed a maternal-fetal PBPK model that can successfully predict maternal drug exposure. To predict fetal drug exposure, the model needs to be populated with drug specific parameters, of which transplacental clearances (active and/or passive) and placental/fetal metabolism of the drug are critical. Herein, we describe in vitro studies in cells/tissue fractions or the perfused human placenta that can be used to determine these drug-specific parameters. In addition, we provide examples whereby this approach has successfully predicted systemic fetal exposure to drugs that passively or actively cross the placenta. Apart from maternal-fetal PBPK models, animal studies also have the potential to estimate fetal drug exposure by allometric scaling. Whether such scaling will be successful is yet to be determined. Here, we review the above approaches to predict fetal drug exposure, outline gaps in our knowledge to make such predictions and map out future research directions that could fill these gaps.


Assuntos
Troca Materno-Fetal , Placenta , Animais , Simulação por Computador , Feminino , Feto/metabolismo , Humanos , Troca Materno-Fetal/fisiologia , Modelos Biológicos , Placenta/metabolismo , Gravidez
6.
Hereditas ; 159(1): 35, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123601

RESUMO

BACKGROUND: Preeclampsia, a multisystem disorder of unknown etiology, is one of the leading causes of maternal and perinatal morbidity and mortality. Identifying sensitive, noninvasive markers can aid its prevention and improve prognosis. microRNAs (miRs), which function as negative regulators of gene expression, are closely related to preeclampsia occurrence and development. Herein we investigated the relationship between the DLK1-Dio3 imprinted miR cluster derived from placental and peripheral blood exosomes of pregnant women with preeclampsia and routine clinical diagnostic indicators, and also determined its potential as a noninvasive diagnostic marker. METHODS: Exosomes were extracted from the placenta and peripheral blood of pregnant women with preeclampsia. RESULTS: qPCR data indicated that the expression level of miRs, such as miR-134, miR-31-5p, miR-655, miR-412, miR-539, miR-409, and miR-496, in pregnant women with preeclampsia was significantly lower than that in healthy controls; miR-31-5p expression was the most different. Gene ontology analysis predicted that genes negatively regulated by miR-31-5p were mainly enriched in cellular entity, cellular process, and binding; moreover, Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that genes were involved in gonadotropin-releasing hormone receptor pathway and other signaling pathways. Correlation analysis revealed that miR-31-5p was significantly negatively correlated with clinical indicators of preeclampsia, such as systolic and diastolic pressure, lactate dehydrogenase, and proteinuria. CONCLUSION: We believe that exosome-derived miR-31-5p can serve as an effective and sensitive biomarker to determine the course of preeclampsia in pregnant women.


Assuntos
Exossomos , MicroRNAs , Pré-Eclâmpsia , Biomarcadores , Exossomos/genética , Exossomos/metabolismo , Feminino , Humanos , Lactato Desidrogenases/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Gravidez , Receptores LHRH/metabolismo
7.
Folia Med Cracov ; 62(1): 73-90, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36088594

RESUMO

BACKGROUND: Preeclampsia (PE) is a condition characterized by high blood pressure and significant proteinuria in pregnant women. It affects about 7% pregnancies and can be cause of fetal and maternal morbidity and mortality. During pregnancy, a physiological overexpression of the Renin-Angiotensin System (RAS) components is observed, including increased plasma Ang II level. Dysregulation of RAS in placenta may contribute to preeclampsia and uterine growth retardation. The aim of the study was to evaluate the Ang I metabolism in human preeclamptic placentas and to compare to normal pregnancies condition. METHOD: Fragments of placental tissues were collected right after ceasarian section from PE and physiological pregnancies. Tissues were incubated in Krebs buffer in the presence of Ang I. Evaluation of Ang I metabolites in incubating fluid was performed by LC/MS/MS method. mRNA expression of main RAS components was measured by RT-PCR. RESULTS: Pattern of angiotensin metabolites did not differ between groups. The main products were Ang 1-7 and Ang II. Comparing to control group, more than 3-fold lower production of Ang II and Ang 1-7 in preeclampsia was observed. mRNA expressions of ACE and AT1 were significantly decreased in pre- eclamptic placentas, whereas higher expression of mRNA of ACE2 and MAS receptor were observed. CONCLUSIONS: Production of Ang 1-7 by PE placentas was significantly lower than in control group. Significantly decreased mRNA expression of ACE and AT1 receptor and lower production of Ang II in placentas of PE patients suggest that placental Ang II/ACE/AT1r pathway could be less important than Ang 1-7/ACE-2/MASr pathway in development of preeclampsia, but this requires further investigations.


Assuntos
Angiotensina I , Pré-Eclâmpsia , Angiotensina I/metabolismo , Feminino , Humanos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Placenta/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Espectrometria de Massas em Tandem
8.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(8): 1129-1135, 2022 Aug 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36097781

RESUMO

OBJECTIVES: Placenta accreta spectrum disorders (PAS) refers to a group of abnormalities in placental adhesion and invasion, which may lead to serious complications such as intractable postpartum hemorrhage. The use of low-level extra-abdominal aortic temporary block during cesarean section may reduce intraoperative bleeding in patients with PAS, but it may also cause ischemia-reperfusion injury. In this study, we intend to investigate the efficacy of low extra-abdominal aortic block in cesarean section for placental implantation disease and its effect on malondialdehyde (MDA) level and superoxide dismutase (SOD) activity, and analyze the severity of ischemia-reperfusion injury caused by them. METHODS: Pregnant women with invasive placenta accreta spectrum disorders who delivered in the Department of Obstetrics and Gynecology of the Third Xiangya Hospital of Central South University from July 2017 to July 2021, were selected, and they were divided into 2 groups. Group A consisted of those who underwent low extra-abdominal aortic block during cesarean section (n=15) and group B consisted of those who did not undergo extra-abdominal aortic block (n=15). The intraoperative bleeding, blood transfusion, hysterectomy and complication rate, postoperative hospital stay and hospitalization expenses were compared between the 2 groups to analyze the efficacy of abdominal aortic block. The biochemical indexes related to ischemia-reperfusion, MDA content and total superoxide dismutase (T-SOD) activity, were measured at the corresponding time points in both groups. The time points of each test were: in group A, before the block of the low extra-abdominal aorta after delivery (A0), 0 h (A1, when the myometrium was started to be sutured), 0.5 h (A2), 2 h (A3), and 4 h (A4) after the open block; in group B, after delivery of the fetus (B0), 0 h (B1), 0.5 h (B2), 2 h (B3), and 4 h (B4) after the myometrium was started to be sutured. Total duration of abdominal aortic block in group A was also recorded. Both groups were observed for sings of edema, ischemia, necrosis and infection in the limbs after surgery. The severity of ischemia-reperfusion injury caused by abdominal aortic block were determined by detecting the relevant biochemical indexes at different moments of reperfusion. RESULTS: The intraoperative bleeding and blood transfusion in group A were less than those in group B, and the difference was statistically significant (P<0.05). There was no significant difference in postoperative hospital stay and hospitalization expenses between the 2 groups (P>0.05). Surgical complications: in group A, the uterus was preserved in all cases, there was 1 bladder injury and 2 pelvic infections; while in group B, there was 1 hysterectomy, 3 bladder injuries, and 3 pelvic infections. Changes in T-SOD and MDA values: compared with A0 before block, the MDA level was significantly elevated in blood at time points A1, A2, and A3, while SOD activity was significantly decreased (P<0.05), and the 2 observed indexes basically returned to A1 level (ischemic period) at 4 h after open block (A4). There was no significant difference in the changes of T-SOD and MDA in group B (P>0.05). Comparison of T-SOD and MDA levels between group A and B: the difference of the 2 indexes was not statistically significant between A0 and B0 (P>0.05), MDA level was not statistically significant between A1 and B1, T-SOD activity at A1 was lower than B1, the difference was statistically significant, at the rest of the same time point, MDA level in group A were higher than that in group B, T-SOD activity in group A were lower than that in group B, the difference was statistically significant (P<0.05). No postoperative limb edema, ischemia, necrosis, or infection occurred in both groups. CONCLUSIONS: Low-level extra-abdominal aortic block effectively reduces bleeding and transfusion during cesarean section for placenta accreta spectrum disorders, resulting in a transient MDA elevation and a decrease of SOD activity, which means causing transient ischemia-reperfusion injury without complications such as limb edema, ischemia, necrosis, and infection.


Assuntos
Infecção Pélvica , Placenta Acreta , Traumatismo por Reperfusão , Aorta Abdominal/metabolismo , Aorta Abdominal/cirurgia , Cesárea , Feminino , Humanos , Isquemia , Necrose , Placenta/metabolismo , Placenta Acreta/cirurgia , Gravidez , Superóxido Dismutase/metabolismo
9.
Biomed Pharmacother ; 154: 113613, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36058146

RESUMO

Acetaminophen is among the most widely used analgesics; however, the proportion and mechanism of transplacental transfer of unbound acetaminophen with actual pharmacological activity remain unknown. Our hypothesis is that acetaminophen gradually penetrates the blood-placenta barrier to reach the fetus. A multiple microdialysis coupled to liquid chromatography with photodiode array detection method was developed to monitor acetaminophen levels in the maternal blood, placenta, fetus, and amniotic fluid of a pregnant rat and investigate this hypothesis. The pharmacokinetic data indicates that acetaminophen exhibits a nonlinear behavior in the maternal blood within the dosage regimen of 100 and 300 mg/kg. In addition, acetaminophen penetrates the placenta, fetus, and amniotic fluid during treatment. The transplacental transfer ratio represented by the area under the concentration curve (AUC) ratio for the conceptus (the collective term for the fetus, placenta, and amniotic fluid) and maternal blood (AUCtissue/AUCblood) was approximately 11-23 % after acetaminophen (100 and 300 mg/kg) administration. However, the transporter of multidrug resistance-associated protein (MRP) inhibitor MK-571 did not significantly change the transplacental transfer ratio. This basic study provides constructive information for the clinical application of acetaminophen in pregnant women.


Assuntos
Acetaminofen , Troca Materno-Fetal , Acetaminofen/metabolismo , Líquido Amniótico/metabolismo , Animais , Cromatografia Líquida , Feminino , Feto/metabolismo , Humanos , Placenta/metabolismo , Gravidez , Ratos
10.
J Neuroinflammation ; 19(1): 221, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071475

RESUMO

BACKGROUND: Mesenchymal stem cell (MSCs)-derived small Extracellular Vesicles (sEVs) are considered as a new cell-free therapy for pain caused by nerve injury, but whether human placental mesenchymal stem cell-derived sEVs relieve pain in sciatic nerve injury and its possible mechanism are still unclear. In this study, we investigated the roles of hPMSCs-derived sEVs and related mechanisms in neuropathic pain. METHODS: The spared nerve injury (SNI) mouse model was employed. Intrathecal injection of sEVs or miR-26a-5p agomir was performed on the seventh day of modeling, to study its anti-nociceptive effect. sEVs' miRNA sequencing (miRNA-Seq) and bioinformatics analysis were performed to study the downstream mechanisms of miRNAs. RT-qPCR, protein assay and immunofluorescence were used for further validation. RESULTS: A single intrathecal injection of sEVs durably reversed mechanical hypersensitivity in the left hind paw of mice with partial sciatic nerve ligation. Immunofluorescence studies found that PKH26-labeled sEVs were visible in neurons and microglia in the dorsal horn of the ipsilateral L4/5 spinal cord and more enriched in the ipsilateral. According to miRNA-seq results, we found that intrathecal injection of miR-26a-5p agomir, the second high counts microRNA in hPMSCs derived sEVs, significantly suppressed neuropathic pain and neuroinflammation in SNI mice. Bioinformatics analysis and dual-luciferase reporter gene analysis identified Wnt5a as a direct downstream target gene of miR-26a-5p. The results showed that overexpression of miR-26a-5p in vivo could significantly reduce the expression level of Wnt5a. In addition, Foxy5, a mimetic peptide of Wnt5a, can significantly reverse the inhibitory effect of miR-26a-5p on neuroinflammation and neuropathic pain, and at the same time, miR-26a-5p can rescue the effect of Foxy5 by overexpression. CONCLUSIONS: We reported that hPMSCs derived sEVs as a promising therapy for nerve injury induced neuropathic pain. In addition, we showed that the miR-26a-5p in the sEVs regulated Wnt5a/Ryk/CaMKII/NFAT partly take part in the analgesia through anti-neuroinflammation, which suggests an alleviating pain effect through non-canonical Wnt signaling pathway in neuropathic pain model in vivo.


Assuntos
Antagomirs , Vesículas Extracelulares , MicroRNAs , Neuralgia , Animais , Antagomirs/farmacologia , Modelos Animais de Doenças , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neuralgia/metabolismo , Placenta/metabolismo , Gravidez , Receptores Proteína Tirosina Quinases , Proteína Wnt-5a/genética
11.
Dis Markers ; 2022: 1664474, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046373

RESUMO

Background: Increasing evidence reveals that iron deficiency during pregnancy causes adverse pregnancy outcomes. Thus far, the mechanisms underlying iron deficiency-associated preterm birth are mostly limited to animal studies. Whether the suggested mechanisms exist in human requires further investigation. The goal of this study was to characterize the iron metabolism in both the maternal side and fetal side in pregnant women with preterm birth. Methods: Serum and placenta samples were collected from 42 pregnant women divided into four groups according to the gestational week. Indicators of iron metabolism, including serum iron, serum hepcidin, placental tissue iron, ferroportin (FPN), transferrin receptor 1 (TfR1), and ferritin, were surveyed using enzyme-linked immunosorbent assays (Elisa), Western blots, and real-time quantitative polymerase chain reactions (qRT-PCR). Results: Significant reduction of maternal serum iron was observed in women with preterm birth relative to those with full-term birth, indicative of worsen iron deficiency in those mothers with preterm birth. Meanwhile, the maternal hepcidin levels were notably diminished in women with preterm birth, whereas the fetal hepcidin levels were comparable between the two groups. Moreover, the placental iron stores were remarkably reduced in the preterm group, associated with reduced concentration of TfR1 and increased FPN concentration relative to the normal controls. In other words, the ratio of placental FPN mass to TfR1 mass (PIDI index) was strikingly increased in the preterm group. Conclusions: Dysregulated iron homeostasis in both the maternal and fetal sides was implicated in preterm births, and disordered regulations in maintaining the placental iron equilibrium were also presumed to account for the compromised fetal iron supply.


Assuntos
Deficiências de Ferro , Nascimento Prematuro , Feminino , Feto/metabolismo , Hepcidinas , Humanos , Recém-Nascido , Ferro , Placenta/metabolismo , Gravidez , Nascimento Prematuro/metabolismo
12.
Reprod Health ; 19(1): 188, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064716

RESUMO

BACKGROUND: Pre-eclampsia is a leading cause of maternal mortality and morbidity that involves pregnancy-related stressors on the maternal cardiovascular and metabolic systems. As nutrition is important to support optimal development of the placenta and for the developing fetus, maternal diets may play a role in preventing pre-eclampsia. The purpose of this scoping review is to map the maternal nutritional deficiencies and imbalances associated with pre-eclampsia incidence and discuss evidence consistency and linkages with current understandings of the etiology of pre-eclampsia. METHODS: A narrative scoping review was conducted to provide a descriptive account of available research, summarize research findings and identify gaps in the evidence base. Relevant observational studies and reviews of observational studies were identified in an iterative two-stage process first involving electronic database searches then more sensitive searches as familiarity with the literature increased. Results were considered in terms of their consistency of evidence, effect sizes and biological plausibility. RESULTS: The review found evidence for associations between nutritional inadequacies and a greater risk of pre-eclampsia. These associations were most likely mediated through oxidative stress, inflammation, maternal endothelial dysfunction and blood pressure in the pathophysiology of pre-eclampsia. Maternal nutritional risk factors for pre-eclampsia incidence with the strongest consistency, effect and biological plausibility include vitamin C and its potential relationship with iron status, vitamin D (both on its own and combined with calcium and magnesium), and healthy dietary patterns featuring high consumption of fruits, vegetables, whole grains, fish, seafood and monounsaturated vegetable oils. Foods high in added sugar, such as sugary drinks, were associated with increased risk of pre-eclampsia incidence. CONCLUSION: A growing body of literature highlights the involvement of maternal dietary factors in the development of pre-eclampsia. Our review findings support the need for further investigation into potential interactions between dietary factors and consideration of nutritional homeostasis and healthy dietary patterns. Further research is recommended to explore gestational age, potential non-linear relationships, dietary diversity and social, cultural contexts of food and meals.


Pre-eclampsia is a condition of high blood pressure during the second half of pregnancy with signs of damage to another organ system, often the liver and kidneys. It is a serious and potentially deadly disease and is the second top cause of deaths related to pregnancy and childbirth globally. Though the exact cause of pre-eclampsia is unclear, researchers have discovered that pre-eclampsia develops through abnormal development of the placenta, which is the interface between the growing baby and the mother in the womb. The placenta helps to transfer nutrients, oxygen and waste between the mother and fetus. Nutrition has important roles to play in the development of the placenta and certain vitamins and minerals have clinical properties that may help prevent pre-eclampsia. We conducted a review to summarize observational studies on maternal nutritional risk factors associated with the development of pre-eclampsia. Promising maternal dietary factors that fit with current understandings of how pre-eclampsia develops include vitamin C and its potential relationship with iron, calcium and vitamin D. Healthy dietary patterns with high consumption of fruits, vegetables, whole grains, fish and seafood and monounsaturated vegetable oils are likely beneficial. Foods high in added sugar, such as sugary drinks, may be linked to higher rates of developing pre-eclampsia. Instead of focusing on single nutrient deficiencies, our findings support a broader approach to explore interrelationships between dietary factors and balanced healthy dietary intake for the prevention of pre-eclampsia.


Assuntos
Pré-Eclâmpsia , Dieta/efeitos adversos , Feminino , Humanos , Placenta/metabolismo , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/etiologia , Gravidez , Fatores de Risco , Vitamina D , Vitaminas
13.
J Zhejiang Univ Sci B ; 23(9): 747-759, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36111571

RESUMO

The mechanisms underlying pregnancy complications caused by advanced maternal age (AMA) remain unclear. We analyzed the cellular signature and transcriptomes of human placentas in AMA women to elucidate these mechanisms. Placental tissues from two AMA women and two controls were used for single-cell RNA-sequencing (scRNA-seq). Controls consisted of AMA women who did not experience any pregnancy complications and pregnant women below the age of 35 years without pregnancy complications. Trophoblast cells were obtained from the placentas of another six pregnant women (three AMA women and three controls), and in-vitro transwell assays were conducted to observe the cell invasion ability. Thirty additional samples (from 15 AMA women and 15 controls) were analyzed to verify the specific expression of serine protease inhibitor clade E member 1 (SERPINE1). Preliminary study of the role of SERPINE1 in cell invasion was carried out with HTR8-S/Vneo cells. High-quality transcriptomes of 27 |607 cells were detected. Three types of trophoblast cells were detected, which were further classified into eight subtypes according to differences in gene expression and Gene Ontology (GO) function. We identified 110 differentially expressed genes (DEGs) in trophoblast cells between the AMA and control groups, and the DEGs were enriched in multiple pathways related to cell invasion. In-vitro transwell assays suggested that the invading trophoblast cells in AMA women were reduced. SERPINE1 was specifically expressed in the trophoblast, and its expression was higher in AMA women (P<0.05). Transfection of human SERPINE1 (hSERPINE1) into HTR8-S/Vneo trophoblast cells showed fewer invading cells in the hSERPINE1 group. Impaired cell invasion may underlie the increased risk of adverse pregnancy outcomes in AMA women. Abnormal expression of SERPINE1 in extravillous trophoblast (EVT) cells appears to play an important role.


Assuntos
Placenta , Complicações na Gravidez , Adulto , Linhagem Celular , Movimento Celular , Feminino , Humanos , Idade Materna , Placenta/metabolismo , Gravidez , Gestantes , RNA/metabolismo , Inibidores de Serino Proteinase/metabolismo
14.
Int J Mol Sci ; 23(17)2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36077527

RESUMO

The abnormal implantation of the trophoblast during the first trimester of pregnancy precedes the appearance of the clinical manifestations of preeclampsia (PE), which is a hypertensive disorder of pregnancy. In a previous study, which was carried out in a murine model of PE that was induced by NG-nitro-L-arginine methyl ester (L-NAME), we observed that the intravenous administration of fibroblast growth factor 2 (FGF2) had a hypotensive effect, improved the placental weight gain and attenuated the fetal growth restriction, and the morphological findings that were induced by L-NAME in the evaluated tissues were less severe. In this study, we aimed to determine the effect of FGF2 administration on the placental gene expression of the vascular endothelial growth factor (VEGFA), VEGF receptor 2 (VEGFR2), placental growth factor, endoglin (ENG), superoxide dismutase 1 (SOD1), catalase (CAT), thioredoxin (TXN), tumor protein P53 (P53), BCL2 apoptosis regulator, Fas cell surface death receptor (FAS), and caspase 3, in a Sprague Dawley rat PE model, which was induced by L-NAME. The gene expression was determined by a real-time polymerase chain reaction using SYBR green. Taking the vehicle or the L-NAME group as a reference, there was an under expression of placental VEGFA, VEGFR2, ENG, P53, FAS, SOD1, CAT, and TXN genes in the group of L-NAME + FGF2 (p < 0.05). The administration of FGF2 in the murine PE-like model that was induced by L-NAME reduced the effects that were generated by proteinuria and the increased BP, as well as the response of the expression of genes that participate in angiogenesis, apoptosis, and OS. These results have generated valuable information regarding the identification of molecular targets for PE and provide new insights for understanding PE pathogenesis.


Assuntos
Fator 2 de Crescimento de Fibroblastos , Pré-Eclâmpsia , Animais , Modelos Animais de Doenças , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Expressão Gênica , Humanos , NG-Nitroarginina Metil Éster/efeitos adversos , Placenta/metabolismo , Fator de Crescimento Placentário/genética , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/induzido quimicamente , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/genética , Gravidez , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase-1/genética , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Epigenomics ; 14(15): 897-911, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36073148

RESUMO

Aim: The placenta-brain axis reflects a developmental linkage where disrupted placental function is associated with impaired neurodevelopment later in life. Placental gene expression and the expression of epigenetic modifiers such as miRNAs may be tied to these impairments and are understudied. Materials & methods: The expression levels of mRNAs (n = 37,268) and their targeting miRNAs (n = 2083) were assessed within placentas collected from the ELGAN study cohort (n = 386). The ELGAN adolescents were assessed for neurocognitive function at age 10 and the association with placental mRNA/miRNAs was determined. Results: Placental mRNAs related to inflammatory and apoptotic processes are under miRNA control and associated with cognitive impairment at age 10. Conclusion: Findings highlight key placenta epigenome-brain relationships that support the developmental origins of health and disease hypothesis.


Children born extremely preterm are at increased risk for neurodevelopmental impairments such as cerebral palsy, intellectual disability and autism. The biological processes that lead to these impairments likely begin before birth and involve altered placental function. In this study, the authors analyzed placental genomic and epigenomic data from children who were born extremely preterm in relation to cognitive assessments at 10 years of age. They examined the differences between the expression of placental genes and molecules that influence the expression of placental genes, comparing children who had impaired cognition at 10 years with children who did not. The results demonstrated elevated expression levels of genes involved in inflammatory processes and molecules that control the expression of these genes within the placentas of children who had impaired cognition at age 10.


Assuntos
Disfunção Cognitiva , MicroRNAs , Adolescente , Encéfalo , Criança , Disfunção Cognitiva/genética , Epigenoma , Epigenômica , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Placenta/metabolismo , Gravidez , Transcriptoma
16.
Psychopharmacology (Berl) ; 239(10): 3355-3366, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36063206

RESUMO

RATIONALE: Serotonin (5-HT) is a monoamine neuromodulator that plays a key role in the organization of the central nervous system. 5-HT alterations may be associated to the emergence of social deficits and psychiatric disorders, including anxiety, depression, and substance abuse disorders. Notably, disruption of the 5-HT system during sensitive periods of development seems to exert long-term consequences, including altered anxiety responses and problematic use of alcohol. OBJECTIVE: We analyzed, in mice, the effects of transient 5-HT depletion at gestation (a developmental stage when medial prefrontal cortex (mPFC) 5-HT levels depend exclusively on placental 5-HT availability) on 5-HT central synthesis and reuptake at weaning. We also explored if 5-HT disruption at the embryonic stage influences behavioral outcomes that may serve as a proxy for autistic- or anxiety-like phenotypes. METHODS: C57/BL6 male and female mice, born from dams treated with a 5-HT synthesis inhibitor (PCPA; 4-Chloro-DL-phenylalanine methyl ester hydrochloride) at gestational days (G)13.5-16.5, were subjected to a behavioral battery that assesses social preference and novelty, compulsive behavior, stereotypies, and ethanol's anti-anxiety effects, at postnatal days (P) 21-28. Afterwards, expression of the genes that encode for 5-HT synthesis (Tph2) and SERT (5-HT transporter) were analyzed in mPFC via real-time RT-PCR. Dopamine 2 receptor (D2R) expression was also analyzed via RT-PCR to further explore possible effects of PCPA on dopaminergic transmission. RESULTS: Transient 5-HT disruption at G13.5-16.5 reduced Tph2 expression of both male and female mice in mPFC at P23. Notably, female mice also exhibited higher SERT expression and reduced D2R expression in mPFC. Mice derived from 5-HT depleted dams displayed heightened compulsive behavior at P21, when compared to control mice. Alcohol anti-anxiety effects at early adolescence (P28) were exhibited by mice derived from 5-HT depleted dams, but not by control counterparts. No social deficits or stereotyped behaviors were observed. CONCLUSION: Transient 5-HT inhibition at gestation resulted in altered expression of genes involved in 5-HT synthesis and reuptake in mPFC at weaning, a period in which the 5-HT system is still developing. These alterations may exert lingering effects, which translate to significant compulsivity and heightened sensitivity to the anxiolytic effects of alcohol at early adolescence.


Assuntos
Ansiolíticos , Serotonina , Animais , Ansiolíticos/farmacologia , Comportamento Animal , Dopamina/metabolismo , Etanol/farmacologia , Feminino , Fenclonina/farmacologia , Humanos , Masculino , Camundongos , Placenta/metabolismo , Gravidez , Piridinolcarbamato , Serotonina/metabolismo , Desmame
17.
J Transl Med ; 20(1): 400, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064413

RESUMO

BACKGROUND: An imbalance in the expression of vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) during pregnancy plays an important role in the pathogenesis of gestational diabetes mellitus (GDM) and eclampsia. VEGF and its receptors change during the regulation of blood vessels as a result of risk factors such as familial genetics. These modifications include loss of original balance of serological indicators, upregulation or downregulation of growth factor indicators, and changes in the placenta, kidney, liver and other organs to varying degrees of damage. This has an impact on both the pregnant woman's and the fetus's health. MAIN BODY: This paper summarizes the mechanisms of unbalanced VEGF and receptor expression based on data from relevant literature on GDM and eclampsia. An Imbalance in VEGF and its binding receptor is often associated with the occurrence of multiple pregnancy disorders. In recent years, researchers have focused on the potential role of VEGF and its receptors in the development of GDM and eclampsia. CONCLUSION: This paper summarizes the different VEGF subtypes and their binding receptors, as well as mechanisms that cause GDM and eclampsia, in order to provide valuable data to inform monitoring, diagnosis, and prognosis.


Assuntos
Diabetes Gestacional , Eclampsia , Pré-Eclâmpsia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Eclampsia/metabolismo , Feminino , Humanos , Placenta/metabolismo , Gravidez , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Int J Mol Sci ; 23(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36076929

RESUMO

Previously, we demonstrated that the proton pump inhibitor, esomeprazole magnesium hydrate (MH), could have potential as a repurposed treatment against preeclampsia, a serious obstetric condition. In this study we investigate the difference in the preclinical effectiveness between 100 µM of esomeprazole MH and its hydration isomer, esomeprazole magnesium trihydrate (MTH). Here, we found that both treatments reduced secretion of sFLT-1 (anti-angiogenic factor) from primary cytotrophoblast, but only esomeprazole MH reduced sFLT-1 secretion from primary human umbilical vein endothelial cells (assessed via ELISA). Both drugs could mitigate expression of the endothelial dysfunction markers, vascular cell adhesion molecule-1 and endothelin-1 (via qPCR). Neither esomeprazole MH nor MTH quenched cytotrophoblast reactive oxygen species production in response to sodium azide (ROS assay). Finally, using wire myography, we demonstrated that both compounds were able to induce vasodilation of human omental arteries at 100 µM. Esomeprazole is safe to use in pregnancy and a candidate treatment for preeclampsia. Using primary human tissues and cells, we validated that esomeprazole is effective in enhancing vascular relaxation, and can reduce key factors associated with preeclampsia, including sFLT-1 and endothelial dysfunction. However, esomeprazole MH was more efficacious than esomeprazole MTH in our in vitro studies.


Assuntos
Pré-Eclâmpsia , Biomarcadores/metabolismo , Esomeprazol/metabolismo , Esomeprazol/farmacologia , Esomeprazol/uso terapêutico , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hidróxido de Magnésio , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
J Hypertens ; 40(10): 2022-2036, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36052525

RESUMO

OBJECTIVE: Biomarkers have become important in the prognosis and diagnosis of various diseases. High-throughput methods, such as RNA sequencing facilitate the detection of differentially expressed genes (DEGs), hence potential biomarker candidates. Individual studies suggest long lists of DEGs, hampering the identification of clinically relevant ones. Concerning preeclampsia - a major obstetric burden with high risk for adverse maternal and/or neonatal outcomes - limitations in diagnosis and prediction are still important issues. We, therefore, developed a workflow to facilitate the screening for biomarkers. METHODS: On the basis of the tool DESeq2, a comprehensive workflow for identifying DEGs was established, analyzing data from several publicly available RNA-sequencing studies. We applied it to four RNA-sequencing datasets (one blood, three placenta) analyzing patients with preeclampsia and normotensive controls. We compared our results with other published approaches and evaluated their performance. RESULTS: We identified 110 genes that are dysregulated in preeclampsia, observed in at least three of the studies analyzed, six even in all four studies. These included FLT-1, TREM-1, and FN1, which either represent established biomarkers at protein level, or promising candidates based on recent studies. For comparison, using a published meta-analysis approach, 5240 DEGs were obtained. CONCLUSION: This study presents a data analysis workflow for preeclampsia biomarker screening, capable of identifying promising biomarker candidates, while drastically reducing the numbers of candidates. Moreover, we were also able to confirm its performance for heart failure. This approach can be applied to additional diseases for biomarker identification, and the set of DEGs identified in preeclampsia represents a resource for further studies.


Assuntos
Pré-Eclâmpsia , Biomarcadores , Feminino , Humanos , Recém-Nascido , Placenta/metabolismo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Gravidez , RNA , Análise de Sequência de RNA
20.
Sci Rep ; 12(1): 14937, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056073

RESUMO

Preterm newborns are more likely to suffer from infectious diseases at birth compared to children delivered at term. Whether this is due to compromised cellular, humoral, or organ-specific development remains unclear. To begin to define whether maternal-fetal antibody transfer profiles differ across preterm (PT) and fullterm (FT) infants, the overall quantity and functional quality of an array of 24 vaccine-, endemic pathogen-, and common antigen-specific antibodies were assessed across a cohort of 11 PT and 12 term-delivered maternal:infant pairs from birth through week 12. While total IgG levels to influenza, pneumo, measles, rubella, EBV, and RSV were higher in FT newborns, selective Fc-receptor binding antibodies was noted in PT newborns. In fact, near equivalent antibody-effector functions were observed across PT and FT infants, despite significant quantitative differences in transferred antibody levels. Moreover, temporal transfer analysis revealed the selective early transfer of FcRn, FcγR2, and FcγR3 binding antibodies, pointing to differential placental sieving mechanisms across gestation. These data point to selectivity in placental transfer at distinct gestational ages, to ensure that children are endowed with the most robust humoral immunity even if born preterm.


Assuntos
Recém-Nascido Prematuro , Rubéola (Sarampo Alemão) , Anticorpos Antivirais/metabolismo , Criança , Feminino , Idade Gestacional , Humanos , Imunoglobulina G/metabolismo , Lactente , Recém-Nascido , Placenta/metabolismo , Gravidez
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