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1.
Artigo em Inglês | MEDLINE | ID: mdl-39106300

RESUMO

Preterm birth remains a worldwide health concern due to ongoing challenges in prediction and prevention. Current predictors are limited by poor performance, need for invasive sampling, and an inability to identify patients in a timely fashion to allow for effective intervention. The multiple etiologies of preterm birth often have an inflammatory component. Thus, a deeper understanding of the inflammatory mechanisms involved in preterm birth may provide opportunities to identify new predictors of preterm birth. This review will discuss the multiple etiologies of preterm birth, their links to inflammation, current predictors available, and new directions for the field.

2.
J Intern Med ; 295(2): 181-195, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37870937

RESUMO

BACKGROUND: Ferroptosis plays a key role in placental development and physiology, and abnormal ferroptosis has been implicated in trophoblast injury leading to preeclampsia (PE). We hypothesize that leukocytes isolated from PE exhibit increased ferroptosis and that extracellular vesicles contain long non-coding (lnc) RNA/mRNAs that modulate oxidative stress and iron toxicity in vascular endothelial cells. METHODS: We measured the expression of key regulators of ferroptosis in leukocytes and extracellular vesicles as well as circulating biomarkers of iron homeostasis and oxidative stress in plasma from women with/without PE at different timepoints during pregnancy. For markers that were dysregulated, we assessed their temporal correlation with established markers of disease activity and marker of endothelial activation. For markers dysregulated in early pregnancy, we assessed their ability to predict the development of PE. RESULTS: We found decreased lncRNA/mRNAs in leukocytes, but not extracellular vesicles, in PE that may modulate oxidative stress and iron toxicity. This decrease in anti-ferroptotic markers does not appear to be related to maternal disease activity or plasma oxidative stress status but rather to attenuated anti-inflammatory expression in these cells. Circulating ferritin was elevated in PE, supporting the hypothesis that PE represents a disbalance in iron homeostasis. Low lncRNA taurine upregulated gene 1 RNA levels in leukocytes at 22-24 weeks were strongly associated with the development of PE. CONCLUSIONS: Our findings suggest that maternal leukocytes in PE show decreased anti-ferroptotic activity that correlates with anti-inflammatory expression. Moreover, some of these changes in ferroptotic activity appear to precede the development of PE.


Assuntos
Ferroptose , Pré-Eclâmpsia , RNA Longo não Codificante , Feminino , Humanos , Gravidez , Anti-Inflamatórios , Células Endoteliais , Ferro , Leucócitos , Placenta/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
3.
J Clin Microbiol ; 62(3): e0149823, 2024 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-38315022

RESUMO

Sepsis caused by bloodstream infection (BSI) is a major healthcare burden and a leading cause of morbidity and mortality worldwide. Timely diagnosis is critical to optimize clinical outcome, as mortality rates rise every hour treatment is delayed. Blood culture remains the "gold standard" for diagnosis but is limited by its long turnaround time (1-7 days depending on the organism) and its potential to provide false-negative results due to interference by antimicrobial therapy or the presence of mixed (i.e., polymicrobial) infections. In this paper, we evaluated the performance of resistance and pathogen ID/BSI, a direct-from-specimen molecular assay. To reduce the false-positivity rate common with molecular methods, this assay isolates and detects genomic material only from viable microorganisms in the blood by incorporating a novel precursor step to selectively lyse host and non-viable microbial cells and remove cell-free genomic material prior to lysis and analysis of microbial cells. Here, we demonstrate that the assay is free of interference from host immune cells and common antimicrobial agents at elevated concentrations. We also demonstrate the accuracy of this technology in a prospective cohort pilot study of individuals with known sepsis/BSI status, including samples from both positive and negative individuals. IMPORTANCE: Blood culture remains the "gold standard" for the diagnosis of sepsis/bloodstream infection (BSI) but has many limitations which may lead to a delay in appropriate and accurate treatment in patients. Molecular diagnostic methods have the potential for markedly improving the management of such patients through faster turnaround times and increased accuracy. But molecular diagnostic methods have not been widely adopted for the identification of BSIs. By incorporating a precursor step of selective lysis of host and non-viable microorganisms, our resistance and pathogen ID (RaPID)/BSI molecular assay addresses many limitations of blood culture and other molecular assay. The RaPID/BSI assay has an approximate turnaround time of 4 hours, thereby significantly reducing the time to appropriate and accurate diagnosis of causative microorganisms in such patients. The short turnaround time also allows for close to real-time tracking of pathogenic clearance of microorganisms from the blood of these patients or if a change of antimicrobial regimen is required. Thus, the RaPID/BSI molecular assay helps with optimization of antimicrobial stewardship; prompt and accurate diagnosis of sepsis/BSI could help target timely treatment and reduce mortality and morbidity in such patients.


Assuntos
Anti-Infecciosos , Bacteriemia , Infecções Bacterianas , Doenças Transmissíveis , Sepse , Humanos , Projetos Piloto , Sepse/diagnóstico , Bacteriemia/diagnóstico
4.
Am J Obstet Gynecol ; 231(3): 363.e1-363.e11, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38825028

RESUMO

BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform. OBJECTIVE: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features. STUDY DESIGN: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death). RESULTS: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values. CONCLUSION: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.


Assuntos
Biomarcadores , Fator de Crescimento Placentário , Pré-Eclâmpsia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Fator de Crescimento Placentário/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Biomarcadores/sangue , Estudos de Coortes , Curva ROC , Índice de Gravidade de Doença , Valor Preditivo dos Testes , Idade Gestacional
5.
BMC Med ; 21(1): 458, 2023 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-37996819

RESUMO

BACKGROUND: Circulating extracellular vesicles (EVs) are increased in preeclampsia (PE) and are associated with severity and progression. We examined in this exploratory cohort study if the mRNAs and long noncoding RNAs (lncRNAs) in plasma-derived EVs were dysregulated in PE compared to normal pregnancy and display different temporal patterns during gestation. METHODS: We isolated EVs from plasma at weeks 22-24 and 36-38 in women with and without PE (n=7 in each group) and performed RNA-seq, focusing on mRNAs and lncRNAs. We validated highly expressed mitochondrial and platelet-derived RNAs discovered from central pathways in 60 women with/without PE. We examined further one of the regulated RNAs, noncoding mitochondrially encoded tRNA alanine (MT-TA), in leukocytes and plasma to investigate its biomarker potential and association with clinical markers of PE. RESULTS: We found abundant levels of platelet-derived and mitochondrial RNAs in EVs. Expression of these RNAs were decreased and lncRNAs increased in EVs from PE compared to without PE. These findings were further validated by qPCR for mitochondrial RNAs MT-TA, MT-ND2, MT-CYB and platelet-derived RNAs PPBP, PF4, CLU in EVs. Decreased expression of mitochondrial tRNA MT-TA in leukocytes at 22-24 weeks was strongly associated with the subsequent development of PE. CONCLUSIONS: Platelet-derived and mitochondrial RNA were highly expressed in plasma EVs and were decreased in EVs isolated from women with PE compared to without PE. LncRNAs were mostly increased in PE. The MT-TA in leukocytes may be a useful biomarker for prediction and/or early detection of PE.


Assuntos
Vesículas Extracelulares , Pré-Eclâmpsia , RNA Longo não Codificante , Gravidez , Humanos , Feminino , RNA Mitocondrial/genética , RNA Mitocondrial/metabolismo , Pré-Eclâmpsia/genética , Estudos de Coortes , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , RNA Mensageiro/metabolismo , Biomarcadores/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo
6.
Proc Natl Acad Sci U S A ; 117(27): 15772-15777, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581122

RESUMO

During pregnancy, invading HLA-G+ extravillous trophoblasts (EVT) play a key role in placental development, uterine spiral artery remodeling, and prevention of detrimental maternal immune responses to placental and fetal antigens. Failures of these processes are suggested to play a role in the development of pregnancy complications, but very little is known about the underlying mechanisms. Here we present validated methods to purify and culture primary HLA-G+ EVT from the placental disk and chorionic membrane from healthy term pregnancy. Characterization of HLA-G+ EVT from term pregnancy compared to first trimester revealed their unique phenotypes, gene expression profiles, and differing capacities to increase regulatory T cells (Treg) during coculture assays, features that cannot be captured by using surrogate cell lines or animal models. Furthermore, clinical variables including gestational age and fetal sex significantly influenced EVT biology and function. These methods and approaches form a solid basis for further investigation of the role of HLA-G+ EVT in the development of detrimental placental inflammatory responses associated with pregnancy complications, including spontaneous preterm delivery and preeclampsia.


Assuntos
Antígenos HLA-G/imunologia , Imunidade Inata/genética , Placentação/imunologia , Pré-Eclâmpsia/imunologia , Linhagem Celular , Movimento Celular/imunologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Humanos , Relações Materno-Fetais , Placenta/imunologia , Placenta/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Primeiro Trimestre da Gravidez , Trofoblastos/imunologia
7.
Clin Gastroenterol Hepatol ; 20(11): 2542-2550.e8, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-34798335

RESUMO

BACKGROUND & AIMS: Recently, metabolic dysfunction-associated fatty liver disease (MAFLD), rather than nonalcoholic fatty liver disease (NAFLD), was proposed to better describe liver disease associated with metabolic dysfunction (MD). In this study, we attempted to investigate the impact of MAFLD on pregnancy complications. METHODS: The current study is a secondary analysis of a multicenter prospective cohort designed to examine the risk of NAFLD during pregnancy. In the first trimester, enrolled pregnant women were evaluated for hepatic steatosis by liver ultrasonography, and blood samples were collected for biochemical measurements. The study population was divided into 3 groups: no NAFLD, hepatic steatosis but without metabolic dysfunction (non-MD NAFLD), and MAFLD. The primary outcome was the subsequent development of adverse pregnancy outcomes, including gestational diabetes mellitus, pregnancy-associated hypertension, preterm birth, and fetal growth abnormalities. RESULTS: The study population consisted of 1744 pregnant women, including 1523 with no NAFLD, 43 with non-MD NAFLD, and 178 with MAFLD. The risk of subsequent development of adverse pregnancy outcomes was higher in MAFLD than in non-MD NAFLD (adjusted odds ratio, 4.03; 95% CI, 1.68-9.67), whereas the risk was not significantly different between no NAFLD and non-MD NAFLD. Among women with no NAFLD, the presence of MD increased the risk of adverse pregnancy outcomes. However, women with MAFLD were at higher risk for adverse pregnancy outcomes than women with no NAFLD without MD or those with no NAFLD with MD. CONCLUSIONS: In pregnant women, MAFLD may be associated with an increased risk of subsequent adverse pregnancy outcomes.


Assuntos
Diabetes Gestacional , Hepatopatia Gordurosa não Alcoólica , Nascimento Prematuro , Feminino , Recém-Nascido , Gravidez , Humanos , Resultado da Gravidez/epidemiologia , Estudos Prospectivos , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Diabetes Gestacional/epidemiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia
8.
J Immunol ; 204(12): 3149-3159, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376646

RESUMO

Decidual NK cells (dNK) are the main lymphocyte population in early pregnancy decidual mucosa. Although dNK decrease during pregnancy, they remain present in decidual tissues at term. First trimester dNK facilitate trophoblast invasion, provide protection against infections, and were shown to have many differences in their expression of NKRs, cytokines, and cytolytic capacity compared with peripheral blood NK cells (pNK). However, only limited data are available on the phenotype and function of term pregnancy dNK. In this study, dNK from human term pregnancy decidua basalis and decidua parietalis tissues were compared with pNK and first trimester dNK. Profound differences were found, including: 1) term pregnancy dNK have an increased degranulation response to K562 and PMA/ionomycin but lower capacity to respond to human CMV-infected cells; 2) term pregnancy dNK are not skewed toward recognition of HLA-C, as was previously shown for first trimester dNK; and 3) protein and gene expression profiles identified multiple differences between pNK, first trimester, and term pregnancy dNK, suggesting term pregnancy dNK are a distinct type of NK cells. Understanding the role of dNK throughout pregnancy is of high clinical relevance for studies aiming to prevent placental inflammatory disorders as well as maternal-to-fetal transmission of pathogens.


Assuntos
Decídua/imunologia , Células Matadoras Naturais/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Células Cultivadas , Feminino , Expressão Gênica/imunologia , Antígenos HLA-C/imunologia , Humanos , Células K562 , Gravidez , Trofoblastos/imunologia
9.
Proc Natl Acad Sci U S A ; 115(40): E9381-E9390, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30232261

RESUMO

Mast cells are critical for allergic and inflammatory responses in which the peptide substance P (SP) and the cytokine IL-33 are involved. SP (0.01-1 µM) administered together with IL-33 (30 ng/mL) to human cultured LAD2 mast cells stimulates a marked increase (P < 0.0001) in secretion of the proinflammatory cytokine IL-1ß. Preincubation of LAD2 (30 min) with the SP receptor (NK-1) antagonists L-733,060 (10 µM) or CP-96345 (10 µM) inhibits (P < 0.001) secretion of IL-1ß stimulated by either SP (1 µM) or SP together with IL-33 (30 ng/mL). Surprisingly, secretion of IL-1ß stimulated by IL-33 is inhibited (P < 0.001) by each NK-1 antagonist. Preincubation with an antibody against the IL-33 receptor ST2 inhibits (P < 0.0001) secretion of IL-1ß stimulated either by IL-33 or together with SP. The combination of SP (1 µM) with IL-33 (30 ng/mL) increases IL-1ß gene expression by 90-fold in LAD2 cells and by 200-fold in primary cultured mast cells from human umbilical cord blood. The combination of SP and IL-33 increases intracellular levels of IL-1ß in LAD2 by 100-fold and gene expression of IL-1ß and procaspase-1 by fivefold and pro-IL-1ß by twofold. Active caspase-1 is present even in unstimulated cells and is detected extracellularly. Preincubation of LAD2 cells with the natural flavonoid methoxyluteolin (1-100 mM) inhibits (P < 0.0001) secretion and gene expression of IL-1ß, procaspase-1, and pro-IL-1ß. Mast cell secretion of IL-1ß in response to SP and IL-33 reveals targets for the development of antiinflammatory therapies.


Assuntos
Interleucina-1beta/metabolismo , Interleucina-33/farmacologia , Luteolina/farmacologia , Mastócitos/metabolismo , Substância P/farmacologia , Compostos de Bifenilo/farmacologia , Caspase 1/metabolismo , Linhagem Celular Tumoral , Humanos , Mastócitos/citologia , Piperidinas/farmacologia
10.
Proc Natl Acad Sci U S A ; 115(2): 385-390, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29259116

RESUMO

Understanding how decidual CD8+ T cell (CD8+ dT) cytotoxicity is regulated and how these cells integrate the competing needs for maternal-fetal tolerance and immunity to infection is an important research and clinical goal. Gene-expression analysis of effector-memory CD8+ dT demonstrated a mixed transcriptional signature of T cell dysfunction, activation, and effector function. High protein expression of coinhibitory molecules PD1, CTLA4, and LAG3, accompanied by low expression of cytolytic molecules suggests that the decidual microenvironment reduces CD8+ dT effector responses to maintain tolerance to fetal antigens. However, CD8+ dT degranulated, proliferated, and produced IFN-γ, TNF-α, perforin, and granzymes upon in vitro stimulation, demonstrating that CD8+ dT are not permanently suppressed and retain the capacity to respond to proinflammatory events, such as infections. The balance between transient dysfunction of CD8+ dT that are permissive of placental and fetal development, and reversal of this dysfunctional state, is crucial in understanding the etiology of pregnancy complications and prevention of congenital infections.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Decídua/metabolismo , Perfilação da Expressão Gênica/métodos , Tolerância Imunológica/genética , Linfócitos T CD8-Positivos/imunologia , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Feminino , Granzimas/genética , Granzimas/metabolismo , Humanos , Tolerância Imunológica/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Perforina/genética , Perforina/metabolismo , Fatores de Tempo
11.
Liver Int ; 40(10): 2417-2426, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32558189

RESUMO

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is an independent predictor of cardiovascular disease (CVD) in non-pregnant adults. Although the biological mechanisms underlying this association are not completely understood, metabolic factors, inflammation, and endothelial dysfunction are likely all involved. The association between NAFLD and pregnancy-associated hypertension (HTN) has not been systematically examined. The aim of this study is to assess the risk of pregnancy-associated HTN in pregnant women with NAFLD. METHODS: This is secondary analysis of a prospective study of healthy pregnant women. Liver ultrasonography was performed at 10-14 weeks of gestation and maternal blood was taken for the measurement of selenoprotein P (SeP), a hepatokine independently associated with both NAFLD and CVD. Pregnancy-associated HTN was defined as the development of gestational HTN, preeclampsia, or eclampsia. RESULTS: Among 877 pregnant women, the risk of developing pregnancy-associated HTN was significantly increased in women with NAFLD compared to those without NAFLD. Grade 2-3 steatosis was a significant predictor of pregnancy-associated HTN, even after adjustment for metabolic risk factors. Circulating levels of SeP were significantly higher in women with versus those without NAFLD (P = .001) and was significantly higher also in women who subsequently developed pregnancy-associated HTN compared with those who did not (P < .005). CONCLUSIONS: Sonographic evidence of NAFLD at 10-14 weeks is an independent predictor of pregnancy-associated HTN. Circulating levels of SeP at that same gestational age are significantly increased in pregnant women with NAFLD who subsequently develop pregnancy-associated HTN.


Assuntos
Doenças Cardiovasculares , Hipertensão , Hepatopatia Gordurosa não Alcoólica , Adulto , Feminino , Humanos , Hipertensão/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Gravidez , Estudos Prospectivos , Fatores de Risco
12.
Am J Obstet Gynecol ; 223(3): 383.e1-383.e7, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32561227

RESUMO

The coronavirus disease 2019 pandemic has significantly disrupted operations in academic departments of obstetrics and gynecology throughout the United States and will continue to affect them in the foreseeable future. It has also created an environment conducive to innovation and the accelerated implementation of new ideas. These departments will need to adapt their operations to accommodate coronavirus disease 2019 and to continue to meet their tripartite mission of clinical excellence, medical education, and women's health research. This "Call to Action" paper from the leaders of American Gynecological and Obstetrical Society and Council of University Chairs of Obstetrics and Gynecology provides a framework to help the leaders of departments of obstetrics and gynecology reimagine and reengineer their operations in light of the current coronavirus disease 2019 crisis and future pandemics.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Ginecologia , Obstetrícia , Pneumonia Viral/epidemiologia , Academias e Institutos , COVID-19 , Educação Médica , Ginecologia/educação , Humanos , Obstetrícia/educação , Pandemias , Segurança do Paciente , SARS-CoV-2 , Sociedades Médicas , Saúde da Mulher
13.
J Korean Med Sci ; 35(10): e73, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32174066

RESUMO

BACKGROUND: Twin-to-twin transfusion syndrome (TTTS) is a serious complication of monochorionic twin pregnancies. It results from disproportionate blood supply to each fetus caused by abnormal vascular anastomosis within the placenta. Amniotic fluid (AF) is an indicator reflecting the various conditions of the fetus, and an imbalance in AF volume is essential for the antenatal diagnosis of TTTS by ultrasound. In this study, two different mass spectrometry quantitative approaches were performed to identify differentially expressed proteins (DEPs) within matched pairs of AF samples. METHODS: We characterized the AF proteome in pooled AF samples collected from donor and recipient twin pairs (n = 5 each) with TTTS by a global proteomics profiling approach and then preformed the statistical analysis to determine the DEPs between the two groups. Next, we carried out a targeted proteomic approach (multiple reaction monitoring) with DEPs to achieve high-confident TTTS-associated AF proteins. RESULTS: A total of 103 AF proteins that were significantly altered in their abundances between donor and recipient fetuses. The majority of upregulated proteins identified in the recipient twins (including carbonic anhydrase 1, fibrinogen alpha chain, aminopeptidase N, alpha-fetoprotein, fibrinogen gamma chain, and basement membrane-specific heparan sulfate proteoglycan core protein) have been associated with cardiac or dermatologic disease, which is often seen in recipient twins as a result of volume overload. In contrast, proteins significantly upregulated in AF collected from donor twins (including IgGFc-binding protein, apolipoprotein C-I, complement C1q subcomponent subunit B, apolipoprotein C-III, apolipoprotein A-II, decorin, alpha-2-macroglobulin, apolipoprotein A-I, and fibronectin) were those previously shown to be associated with inflammation, ischemic cardiovascular complications or renal disease. CONCLUSION: In this study, we identified proteomic biomarkers in AF collected from donor and recipient twins in pregnancies complicated by TTTS that appear to reflect underlying functional and pathophysiological challenges faced by each of the fetuses.


Assuntos
Líquido Amniótico/metabolismo , Transfusão Feto-Fetal/diagnóstico , Proteômica , Biomarcadores/metabolismo , Feminino , Humanos , Recém-Nascido , Placenta/metabolismo , Gravidez , Gravidez de Gêmeos , Diagnóstico Pré-Natal , Proteoma
14.
Int J Mol Sci ; 21(11)2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32521725

RESUMO

Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst-including the downregulation of genes involved in the pro- inflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion-leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed.


Assuntos
Decídua/fisiologia , Endométrio/fisiologia , Animais , Comunicação Autócrina , Biomarcadores , Implantação do Embrião , Feminino , Regulação da Expressão Gênica , Humanos , Comunicação Parácrina , Placentação , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/metabolismo , Complicações na Gravidez/prevenção & controle , Resultado da Gravidez
15.
Diabetologia ; 62(2): 238-248, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30470912

RESUMO

AIMS/HYPOTHESIS: Although there is substantial evidence that non-alcoholic fatty liver disease (NAFLD) is associated with impaired glucose homeostasis, the clinical significance of NAFLD in pregnant women has not been well determined. This study investigates the relationship between NAFLD in the first trimester and the subsequent development of gestational diabetes mellitus (GDM). METHODS: A multicentre, prospective cohort study was conducted in which singleton pregnant Korean women were assessed for NAFLD at 10-14 weeks using liver ultrasound, fatty liver index (FLI) and hepatic steatosis index (HSI). Maternal plasma adiponectin and selenoprotein P concentrations were measured. Participants were screened for GDM using the two-step approach at 24-28 weeks. RESULTS: Six hundred and eight women were included in the final analysis. The prevalence of NAFLD was 18.4% (112/608) and 5.9% (36/608) developed GDM. Participants who developed GDM had a higher prevalence of radiological steatosis (55.6% vs 16.1%; p < 0.001) and higher FLI (40.0 vs 10.7; p < 0.001) and HSI (35.5 vs 29.0; p < 0.001). The risk of developing GDM was significantly increased in participants with NAFLD and was positively correlated with the severity of steatosis. This relationship between NAFLD and GDM remained significant after adjustment for metabolic risk factors, including measures of insulin resistance. Maternal plasma adiponectin and selenoprotein P levels were also correlated with both NAFLD severity and the risk of developing GDM. CONCLUSIONS/INTERPRETATION: NAFLD in early pregnancy is an independent risk factor for GDM. Adiponectin may be a useful biomarker for predicting GDM in pregnant women.


Assuntos
Diabetes Gestacional/diagnóstico , Resistência à Insulina/fisiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Complicações na Gravidez/diagnóstico , Primeiro Trimestre da Gravidez/sangue , Biomarcadores/sangue , Diabetes Gestacional/sangue , Feminino , Humanos , Hepatopatia Gordurosa não Alcoólica/sangue , Gravidez , Complicações na Gravidez/sangue , Fatores de Risco
16.
Int J Mol Sci ; 20(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277367

RESUMO

Iron is an essential element for the survival of most organisms, including humans. Demand for iron increases significantly during pregnancy to support growth and development of the fetus. Paradoxically, epidemiologic studies have shown that excessive iron intake and/or high iron status can be detrimental to pregnancy and is associated with reproductive disorders ranging from endometriosis to preeclampsia. Reproductive complications resulting from iron deficiency have been reviewed elsewhere. Here, we focus on reproductive disorders associated with iron overload and the contribution of ferroptosis-programmed cell death mediated by iron-dependent lipid peroxidation within cell membranes-using preeclampsia as a model system. We propose that the clinical expressions of many reproductive disorders and pregnancy complications may be due to an underlying ferroptopathy (elemental iron-associated disease), characterized by a dysregulation in iron homeostasis leading to excessive ferroptosis.


Assuntos
Ferroptose , Sobrecarga de Ferro/complicações , Pré-Eclâmpsia/etiologia , Reprodução , Feminino , Homeostase , Humanos , Modelos Biológicos , Gravidez
17.
Proteomics ; 16(10): 1581-9, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27001287

RESUMO

Defective deep placentation, involving abnormal transformation of the spiral arteries in the junctional zone of the myometrium, is known to cause significant obstetric complications, such as preeclampsia (PE), fetal growth restriction, and placental infarction leading to fetal death. Serological biomarkers to predict and diagnose PE would help antenatal care and reduce obstetric complications. To discover candidate PE biomarkers, we first performed global proteomic profiling of three pairs of plasma samples obtained from pregnant women in the early second trimester, who subsequently developed PE, and controls to identify candidate proteins that were abundant in the patients. We further evaluated the changes in the expression of PE-representing proteins in stored plasma samples of a cohort that subsequently developed PE and their matched controls by MRM-MS analysis. We identified that both complement C1s subcomponent (C1S) and protein AMBP were elevated in the plasma samples of the PE cohort before the manifestation of clinical disease. We propose that these proteins may be involved in the remodeling process of the spiral arteries even before PE manifestation. These proteins can serve as potential plasma biomarkers to predict the pregnant women having an increased risk of developing PE.


Assuntos
Expressão Gênica , Pré-Eclâmpsia/sangue , Sequência de Aminoácidos , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Gravidez , Proteômica
18.
Cardiovasc Diabetol ; 15: 23, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26842615

RESUMO

BACKGROUND: Gestational diabetes mellitus (GDM) is a significant risk factor for cardiovascular disease (CVD) in later life. Pentraxin 3 (PTX3) is an essential component of innate immunity and independently associated with the risk of developing vascular events. The aim of the study was to examine the relationships between GDM, cardiovascular risk, and plasma PTX3 in pregnancy and at 5 years after the index pregnancy. METHODS: This population-based prospective cohort included 300 women who had an oral glucose tolerance test (OGTT) during pregnancy. Five years later, the OGTT was repeated along with dual-energy x-ray absorptiometry, lipid analysis, and pulse wave velocity analysis. Fasting PTX3 levels were measured four times during pregnancy and at follow-up. RESULTS: PTX3 levels were lower early in pregnancy and at 5 years follow-up in women who developed GDM. PTX3 levels throughout pregnancy were associated with body mass index. Low PTX3 levels in early pregnancy were predictive of an increased apoB/apoA ratio at 5-year follow-up. PTX3 at 5-year follow-up was inversely correlated with multiple metabolic risk factors for CVD, including body composition, arterial stiffness, dyslipidemia and previous GDM. CONCLUSIONS: Our results show that low plasma concentration of PTX3 in early pregnancy is associated with subsequent development of GDM and with an enhanced risk for CVD as estimated by an elevated apoB/apoA ratio at 5 years postpartum.


Assuntos
Apolipoproteína B-100/sangue , Apolipoproteínas A/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/etiologia , Diabetes Gestacional/sangue , Dislipidemias/etiologia , Componente Amiloide P Sérico/metabolismo , Absorciometria de Fóton , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Diabetes Gestacional/diagnóstico , Regulação para Baixo , Dislipidemias/sangue , Dislipidemias/diagnóstico , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Estudos Longitudinais , Gravidez , Estudos Prospectivos , Análise de Onda de Pulso , Medição de Risco , Fatores de Risco , Fatores de Tempo , Rigidez Vascular
19.
Curr Diab Rep ; 16(4): 26, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26879309

RESUMO

With increasing rates of obesity and new diagnostic criteria for gestational diabetes mellitus (GDM), the overall prevalence of GDM is increasing worldwide. Women with GDM have an increased risk of maternal and fetal complications during pregnancy as well as long-term risks including higher prevalence of type 2 diabetes mellitus and cardiovascular disease. In recent years, the role of immune activation and inflammation in the pathogenesis of GDM has gained increasing attention. This monograph explores the current state of the literature as regards the expression of markers of inflammation in the maternal circulation, placenta, and adipose tissue of women with GDM.


Assuntos
Diabetes Gestacional/imunologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Animais , Diabetes Gestacional/metabolismo , Progressão da Doença , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/complicações , Placenta/imunologia , Placenta/metabolismo , Gravidez
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