RESUMO
BACKGROUND: The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother-to-child HBV transmission is a key step towards hepatitis elimination. However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation. METHODS: The maternal and infant outcomes were compared in multi-centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow-ups. To explore the dynamic pre- and postpartum changes in ALT levels, we used a group-based trajectory model for analysing data of 332 women from three prospective studies. RESULTS: After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg-positive rates among 12-month-old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF-treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%). CONCLUSIONS: TAF effectively reduces mother-to-child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment. CLINICAL TRIAL NUMBER: NCT03695029 (ClinicalTrials.gov).
Assuntos
Alanina Transaminase , Alanina , Antivirais , Transmissão Vertical de Doenças Infecciosas , Complicações Infecciosas na Gravidez , Tenofovir , Carga Viral , Humanos , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Feminino , Gravidez , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Antivirais/uso terapêutico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Adulto , Alanina/uso terapêutico , Alanina/análogos & derivados , Alanina Transaminase/sangue , Estudos Prospectivos , Recém-Nascido , Hepatite B/transmissão , Hepatite B/tratamento farmacológico , Hepatite B/prevenção & controle , Adenina/análogos & derivados , Adenina/uso terapêutico , Vírus da Hepatite B/genética , DNA Viral/sangue , LactenteRESUMO
BACKGROUND: We previously demonstrated that pregnant women with a history of cervical insufficiency had a softer anterior cervical lip, shorter cervical length and wider endocervical canal in the first trimester. The aim of this study was to investigate changes in cervical elastography, cervical length, and endocervical canal width in the second trimester after cerclage, and further discuss whether these ultrasound parameters are predictive of preterm delivery. METHODS: This was a secondary analysis of cervical changes in singleton pregnancies after cerclage from January 2016 to June 2018. Cervical elastography, cervical length, and endocervical canal width were measured during the second trimester in the cervical insufficiency group and control group without cervical insufficiency. Strain elastography under transvaginal ultrasound was used to assess cervical stiffness and presented as percentage (strain rate). RESULTS: Among the 339 pregnant women enrolled, 24 had a history of cervical insufficiency and underwent cerclage. Both anterior and posterior cervical lips were significantly softer in the cervical insufficiency group even though they received cerclage (anterior strain rate: 0.18 ± 0.06% vs. 0.13 ± 0.04%; P = 0.001; posterior strain rate: 0.11 ± 0.03% vs. 0.09 ± 0.04%; P = 0.017). Cervical length was also shorter in the cervical insufficiency group (36.3 ± 3.6 mm vs. 38.3 ± 4.6 mm; P = 0.047). However, there was no significant difference in endocervical canal width between the two groups (5.4 ± 0.7 mm vs. 5.6 ± 0.7 mm; P = 0.159). Multivariate logistic regression analysis also revealed significant differences in anterior cervical lip strain rate (adjusted odds ratio [OR], 7.32, 95% confidence interval [CI], 1.70-31.41; P = 0.007), posterior cervical lip strain rate (adjusted OR, 5.22, 95% CI, 1.42-19.18; P = 0.013), and cervical length (adjusted OR, 3.17, 95% CI,1.08-9.29; P = 0.035). Among the four ultrasound parameters, softer anterior cervical lip (P = 0.024) and shorter cervical length (P < 0.001) were significantly related to preterm delivery. CONCLUSIONS: Cervical cerclage can prevent widening of the endocervical canal, but not improve cervical elasticity or cervical length. Measuring anterior cervical elastography and cervical length may be valuable to predict preterm delivery.
Assuntos
Cerclagem Cervical , Técnicas de Imagem por Elasticidade , Nascimento Prematuro , Recém-Nascido , Gravidez , Feminino , Humanos , Colo do Útero/diagnóstico por imagem , Colo do Útero/cirurgia , Nascimento Prematuro/prevenção & controle , Ultrassonografia , Estudos RetrospectivosRESUMO
BACKGROUND: Prenatal infection has been implicated in the development of neuropsychiatric disorders in children. We hypothesised that exposure to lipopolysaccharide during prenatal development could induce anxiety-like behaviour and sensorineural hearing loss in offspring, as well as disrupt neural differentiation during embryonic neural development. METHODS: We simulated prenatal infection in FVB mice and mouse embryonic stem cell (ESC) lines, specifically 46C and E14Tg2a, through lipopolysaccharide treatment. Gene expression profiling analyses and behavioural tests were utilized to study the effects of lipopolysaccharide on the offspring and alterations in toll-like receptor (TLR) 2-positive and TLR4-positive cells during neural differentiation in the ESCs. RESULTS: Exposure to lipopolysaccharide (25 µg/kg) on gestation day 9 resulted in anxiety-like behaviour specifically in male offspring, while no effects were detected in female offspring. We also found significant increases in the expression of GFAP and CNPase, as well as higher numbers of GFAP + astrocytes and O4+ oligodendrocytes in the prefrontal cortex of male offspring. Furthermore, increased scores for genes related to oligodendrocyte and lipid metabolism, particularly ApoE, were observed in the prefrontal cortex regions. Upon exposure to lipopolysaccharide during the ESC-to-neural stem cell (NSC) transition, Tuj1, Map2, Gfap, O4, and Oligo2 mRNA levels increased in the differentiated neural cells on day 14. In vitro experiments demonstrated that lipopolysaccharide exposure induced inflammatory responses, as evidenced by increased expression of IL1b and ApoB mRNA. CONCLUSIONS: Our findings suggest that prenatal infection at different stages of neural differentiation may result in distinct disturbances in neural differentiation during ESC-NSC transitions. Furthermore, early prenatal challenges with lipopolysaccharide selectively induce anxiety-like behaviour in male offspring. This behaviour may be attributed to the abnormal differentiation of astrocytes and oligodendrocytes in the brain, potentially mediated by ApoB/E signalling pathways in response to inflammatory stimuli.
Assuntos
Ansiedade , Células-Tronco Embrionárias Murinas , Células-Tronco Neurais , Feminino , Animais , Camundongos , Lipopolissacarídeos/toxicidade , Gravidez , Células-Tronco Embrionárias Murinas/citologia , Ansiedade/induzido quimicamente , Células-Tronco Neurais/citologia , Diferenciação Celular , Masculino , Comportamento AnimalRESUMO
Junctional adhesion molecule 3 (JAM3) is involved in epithelial cell junction, cell polarity, and motility. The molecular mechanisms underlying the role of JAM3 in placental dysfunction remain unclear. We hypothesized that JAM3 expression regulates trophoblast fusion, differentiation, proliferation, and apoptosis. Our results revealed that JAM3 was expressed in the cytotrophoblasts and syncytiotrophoblasts of first-trimester and term placental villi. JAM3 expression in cell-cell junctions decreased with the formation of syncytiotrophoblasts. Using trophoblasts as an in vitro model, we observed that forskolin and JAM3 knockdown significantly reduced JAM3 expression and increased syncytium formation. JAM3 knockdown additionally inhibited trophoblast proliferation and increased the number of trophoblasts in the sub-G1 and G2/M phases, indicating cell-cycle disturbance and apoptosis. Cell-cycle arrest was associated with the engagement of checkpoint kinase 2-cell division cycle 25C-cyclin-dependent kinase 1/cyclin B1 signaling. Increased expression of BIM, NOXA, XAF1, cytochrome c, and cleaved caspase-3 further indicated trophoblast apoptosis. Overexpression of JAM3 or recombinant JAM3 protein enhanced trophoblast adhesion and migration, which were inhibited by JAM3 knockdown. JAM3 knockdown induced reactive oxygen species and syncytin 2 expression in trophoblasts. Furthermore, H2O2-induced oxidative stress reduced JAM3 expression in trophoblasts and cell culture supernatants. H2O2 simultaneously induced trophoblast apoptosis. JAM3 expression was significantly decreased in the plasmas and placentas of patients with early-onset severe preeclampsia. Thus, our results show that JAM3 may not only be a structural component of trophoblast cell junctions but also regulates trophoblast fusion, differentiation, proliferation, apoptosis, and motility. Dysregulated trophoblast JAM3 expression is crucial in preeclampsia development.
Assuntos
Molécula C de Adesão Juncional , Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Trofoblastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Molécula C de Adesão Juncional/metabolismo , Peróxido de Hidrogênio , ApoptoseRESUMO
OBJECTIVE/PURPOSE: To identify perinatal antecedents associated with neurodevelopmental impairment for very low birth weight (VLBW) preterm infants at ages 6, 12, and 24 months and the stability of neurodevelopmental assessments. METHODS: A multicenter-based VLBW cohort was recruited, and the mental development index (MDI) and psychomotor development index (PDI) were used to evaluate children's neurodevelopment stages at ages 6, 12, and 24 months. Perinatal risk factors were determined through univariate and multivariate hierarchical linear analyses. Differences and predictability in MDI or PDI scores between ages 6 and 24 months were assessed. RESULTS: Covariates including father's education level; teenage pregnancy, multiple pregnancies; infant's gestational age, gender, and birth weight <999 gm, duration of neonatal intensive care unit stay; and presence of various diseases were adversely associated with poor MDI or PDI scores in 8517 eligible VLBW infants during the study period. Polyhydramnios, emergency cesarean delivery, birth weight of <1250 gm, and periventricular/intraventricular hemorrhage stage I-II were additional risk factors of VLBW infants with an adverse PDI score. An increased number of infants with a MDI or PDI score of <55 at age 24 months was observed. Six-month MDI or PDI assessments had a low ability to predict outcomes at 24 months, with sensitivity and positive predictive values under 60% and specificity and negative predictive values over 85%. CONCLUSION: Multiple perinatal risk factors are associated with poor MDI and PDI scores among VLBW preterm infants. Six-month developmental assessments exhibited low sensitivity and positive predictive values for outcomes at 24 months.
Assuntos
Doenças do Prematuro , Recém-Nascido Prematuro , Adolescente , Peso ao Nascer , Criança , Desenvolvimento Infantil , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Gravidez , TaiwanRESUMO
Slit proteins have been reported to act as axonal repellents in Drosophila; however, their role in the placental microenvironment has not been explored. In this study, we found that human placental multipotent mesenchymal stromal cells (hPMSCs) constitutively express Slit2. Therefore, we hypothesized that Slit2 expressed by hPMSCs could be involved in macrophage migration during placental inflammation through membrane cognate Roundabout (Robo) receptor signaling. In order to develop a preclinical in vitro mouse model of hPMSCs in treatment of perinatal infection, RAW 264.7 cells were used in this study. Slit2 interacted with Robo4 that was highly expressed in RAW 264.7 macrophages: their interaction increased the adhesive ability of RAW 264.7 cells and inhibited migration. Lipopolysaccharide (LPS)-induced CD11bCD18 expression could be inhibited by Slit2 and by hPMSC-conditioned medium (CM). LPS-induced activation of p38 and Rap1 was also attenuated by Slit2 and by hPMSC-CM. Noticeably, these inhibitory effects of hPMSC-CM decreased after depletion of Slit2 from the CM. Furthermore, we found that p38 siRNA inhibited LPS-induced Rap1 expression in RAW 264.7 cells, indicating that Rap1 functions downstream of p38 signaling. p38 siRNA increased cell adhesion and inhibited migration through reducing LPS-stimulated CD11bCD18 expression in RAW 264.7 cells. Thus, hPMSC-derived Slit2 may inhibit LPS-induced CD11bCD18 expression to decrease cell migration and increase adhesion through modulating the activity and motility of inflammatory macrophages in placenta. This may represent a novel mechanism for LPS-induced placental infection.
Assuntos
Movimento Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Placenta/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Animais , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Antígenos CD18/genética , Antígenos CD18/metabolismo , Adesão Celular , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Feminino , Humanos , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , Camundongos , Comunicação Parácrina , Placenta/imunologia , Placenta/patologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/patologia , Células RAW 264.7 , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas rap1 de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome are two uncommon disorders that mimic each other clinically, but are distinct pathophysiologically. This study aimed to compare maternal and neonatal outcomes between AFLP and HELLP syndrome. METHODS: This retrospective cohort study was performed at a tertiary referral center in Taiwan between June 2004 and April 2020. We used the Swansea Criteria to diagnose AFLP, and the Tennessee Classification System to diagnose HELLP syndrome. Maternal characteristics, laboratory data, complications, and neonatal outcomes were compared. We analyzed the categorical variables with Chi-square test or Fisher's exact test and continuous variables with Student's t test or Mann-Whitney U test. Subsequent logistic regression analyses adjusting by potential confounding factors with significant difference were analyzed. RESULTS: During the study period, 21 women had AFLP and 80 women had HELLP syndrome. There was a higher rate of preeclampsia (95.0 % versus 23.8 %) in the HELLP syndrome group compared to the AFLP group. However, the AFLP group had more other maternal complications including jaundice (85.7 % versus 13.8 %), acute kidney injury (61.9 % versus 15.0 %), disseminated intravascular coagulopathy (66.7 % versus 8.8 %), and sepsis (47.6 % versus 10.0 %) compared to the HELLP syndrome group. Nevertheless, higher rates of small for gestational age neonates (57.1 % versus 33.3 %), neonatal respiratory distress syndrome (39.2 % versus 8.3 %) and neonatal sepsis (34.2 % versus 12.5 %) were noted in the HELLP syndrome group. CONCLUSIONS: AFLP is associated with a higher rate of multiple organ dysfunction in mothers, whereas HELLP syndrome is associated with a higher rate of neonatal morbidity.
Assuntos
Fígado Gorduroso/complicações , Síndrome HELLP , Insuficiência de Múltiplos Órgãos/epidemiologia , Sepse Neonatal/epidemiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologia , Adulto , Fígado Gorduroso/diagnóstico , Feminino , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/etiologia , Sepse Neonatal/etiologia , Escores de Disfunção Orgânica , Gravidez , Complicações na Gravidez/diagnóstico , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologia , Estudos Retrospectivos , Taiwan/epidemiologia , Centros de Atenção Terciária/estatística & dados numéricosRESUMO
Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 µg/µL) injection at the same time point; and (ii) UCMSC exosome (1.2 µg/µL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.
Assuntos
Doenças Cocleares/etiologia , Doenças Cocleares/terapia , Exossomos/metabolismo , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical/citologia , Animais , Antineoplásicos/efeitos adversos , Terapia Biológica , Biomarcadores , Cisplatino/efeitos adversos , Doenças Cocleares/patologia , Modelos Animais de Doenças , Exossomos/transplante , Células Ciliadas Auditivas Externas/patologia , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Perda Auditiva/terapia , Imunofenotipagem , Camundongos , MicroRNAs/genética , Proteômica/métodos , Resultado do TratamentoRESUMO
INTRODUCTION: To investigate changes in first trimester cervical elastography, cervical length and endocervical canal width in pregnant women with a history of cervical insufficiency, and further discuss the possibility of using these markers as predictors of cervical insufficiency in early pregnancy. MATERIAL AND METHODS: This was an observational ultrasound study of first trimester cervical changes in singleton pregnancies between January 2016 and June 2018. Cervical elastography, cervical length and endocervical canal width were measured during the first trimester. Strain elastography was used to estimate the softness of anterior and posterior cervical lips and was expressed as percentages (strain rate). RESULTS: Of the 339 pregnant women enrolled, 24 had a history of cervical insufficiency. The anterior cervical lip was significantly softer in the cervical insufficiency group (strain rate: 0.19% ± 0.05% vs 0.11% ± 0.04%; P < .001). Cervical length was significantly shorter in the cervical insufficiency group (36.3 ± 4.8 mm vs 38.3 ± 3.8 mm; P = .014). Endocervical canal width was significantly wider in the cervical insufficiency group (5.7 ± 1.1 mm vs 5.2 ± 0.7 mm; P = .001). Receiver operating characteristic curve analyses revealed that the optimal cut-off values of anterior cervical lip, cervical length and endocervical canal width to confirm the diagnosis of cervical insufficiency were 0.15%, 35.5 mm and 5.75 mm, respectively. In multivariate logistic regression analysis, significant differences were still observed in anterior cervical strain rate (adjusted odds ratio [OR] 53.78, 95% [confidence interval [CI] 11-270; P < .001) and endocervical canal width (adjusted OR, 5.41, 95% CI,1.2-24.7; P = .029). CONCLUSIONS: First trimester cervical elastography is a valuable tool in the assessment of women with a history of cervical insufficiency. The anterior cervical lip was significantly softer in women with a history of cervical insufficiency, and the sensitivity and specificity of anterior cervical lip strain were better than that of cervical length and endocervical canal width.
Assuntos
Colo do Útero/diagnóstico por imagem , Técnicas de Imagem por Elasticidade/métodos , Primeiro Trimestre da Gravidez , Ultrassonografia Pré-Natal/métodos , Incompetência do Colo do Útero/diagnóstico por imagem , Adulto , Medida do Comprimento Cervical/métodos , Feminino , Humanos , Modelos Logísticos , Razão de Chances , Gravidez , Curva ROCRESUMO
BACKGROUND: The process of hospital admission undergone by expectant mothers readily induces feelings of loss of control, anxiousness, and uncertainty. Thus, education to promote the proper response of women to their impending hospital admission may be beneficial in terms of minimizing the number of labor-related hospital trips and the wastage of medical resources. PURPOSE: To explore the effects a labor-admission education program on perceived anxiousness, uncertainty, locus of control, and labor outcomes in expectant mothers. METHODS: A quasi-experimental research design was used to recruit participants. Eligible participants were primipara women who were expected to experience a complications-free pregnancy with a single fetus. A total of 151 participants were enrolled, with 76 assigned to the experimental group and 75 assigned to the control group. The experimental group received the labor and delivery education program intervention while the control group received standard nursing guidance. Participants received the education program in their regular prenatal checkup after the 35th gestational week. The intervention (education program) lasted an hour and included three parts: normal labor signs and appropriate timing of labor admission, self-care strategies at home, and indicators of the onset of labor. A structured questionnaire, including a basic OB/GYN datasheet, the Visual Analogue Scale (VAS) of uncertainty and anxiety, the Labor Agentry Scale (LAS), and birth-outcome information, was used to collect data. Participants completed the three scales at two time points: 1) prior to admission and after the education program and 2) at 3-days postpartum. RESULTS: The findings support the effectiveness of providing a pre-admission education program in terms of lowering perceived uncertainty and anxiousness (p < .001), enhancing the locus of control during birth (p = .001), increasing awareness of the proper time for admission after the onset of labor (p = .001), and reducing the numbers of repeat trips to the hospital (p = .007) and consultations (p < .001). Further, the education program may improve the rate of 3cm-or-greater cervical dilation at admission (p < .001) and reduce the need for induced deliveries (p = .002). CONCLUSIONS / IMPLICATIONS FOR PRACTICE: In the absence of contraindications, this education program should be provided to expectant mothers as an effective method to maximize the duration of the at-home, latent phase of labor in order to increase locus of control over delivery, reduce uncertainty and anxiousness, and attain optimal birth outcomes.
Assuntos
Gestantes/educação , Gestantes/psicologia , Educação Pré-Natal , Ansiedade/prevenção & controle , Feminino , Hospitalização , Humanos , Controle Interno-Externo , Trabalho de Parto , Gravidez , Resultado da Gravidez , Avaliação de Programas e Projetos de Saúde , IncertezaRESUMO
Preterm labor is associated with inflammation and infection. The mechanisms underlying the role of omega-3 fatty acid in inflammasome activation and prevention of preterm labor remain unknown. We hypothesized that omega-3 fatty acid can reduce the rate of preterm birth induced by infection and trophoblast inflammation. In the present study, we found that inflammasome-related molecules and IL-1ß in trophoblasts were activated by TNF-α derived from lipopolysaccharide (LPS)-stimulated THP-1 cell-conditioned medium (CM) and recombinant TNF-α protein. The results demonstrated that stimulation with TNF-α caused lysosomal rupture in trophoblasts, which accelerated cathepsin S (CTSS) diffusion from lysosomes to the cytosol and activated NLRP1 (nacht domain-leucine-rich repeat, and pyd-containing protein 1) and absent in melanoma 2 (AIM2) inflammasomes, thereby increasing IL-1ß secretion. Moreover, in response to LPS challenge, TNF-α increased trophoblast cell death and decreased cell viability through inflammasome and CTSS activation. Stearidonic acid (SDA; 18:4n-3) and docosahexaenoic acid (DHA; 22:6n-3) inhibited inflammasome-related molecule synthesis and CTSS and caspase-1 activation, which further reduced the preterm delivery rate of pregnant mice induced by LPS (92.9 compared with 69.7% (DHA); 92.9 compared with 53.5% (SDA)). Higher expression of TNF-α, IL-1ß, prostaglandin E2, and CTSS, but lower resolvin D1 expression, was observed in preterm pregnant mice than in controls. Similarly, resolvin D1 was highly expressed in women with term delivery compared with women with preterm delivery. Thus, SDA and DHA may attenuate macrophage-derived TNF-α inducing CTSS and inflammasome activation, IL-1ß secretion, and placental trophoblast cell death. These functions are implicated in the preventive effects of SDA and DHA on preterm labor.
Assuntos
Catepsinas/antagonistas & inibidores , Ácidos Graxos Ômega-3/farmacologia , Inflamassomos/efeitos dos fármacos , Trabalho de Parto Prematuro/prevenção & controle , Trofoblastos/enzimologia , Animais , Catepsinas/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Ácidos Docosa-Hexaenoicos/farmacologia , Feminino , Células HEK293 , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Gravidez , Células THP-1RESUMO
The transcription factor glial cells missing 1 (GCM1) regulates trophoblast differentiation and function during placentation. Decreased GCM1 expression is associated with pre-eclampsia, suggesting that abnormal expression of GCM1 target genes may contribute to the pathogenesis of pregnancy complications. Here we identified a novel GCM1 target gene, synapse defective 1 (SYDE1), which encodes a RhoGAP that is highly expressed in human placenta, and demonstrated that SYDE1 promotes cytoskeletal remodelling and cell migration and invasion. Importantly, genetic ablation of murine Syde1 results in small fetuses and placentas with aberrant phenotypes in the placental-yolk sac barrier, maternal-trophoblast interface, and placental vascularization. Microarray analysis revealed altered expression of renin-1, angiotensin I converting enzyme 2, angiotensin II type 1a receptor, and membrane metalloendopeptidase of the renin-angiotensin system in Syde1-knockout placenta, which may compensate for the vascular defects to maintain normal blood pressure. As pregnancy proceeds, growth restriction of the Syde1-/- fetuses and placentas continues, with elevated expression of the Syde1 homologue Syde2 in placenta. Syde2 may compensate for the loss of Syde1 function because SYDE2, but not the GAP-dead SYDE2 mutant, reverses migration and invasion activities of SYDE1-knockdown JAR trophoblast cells. Clinically, we further detected decreased SYDE1 expression in preterm and term IUGR placentas compared with gestational age-matched controls. Our study suggests a novel mechanism for GCM1 and SYDE1 in regulation of trophoblast cell migration and invasion during placental development and that decreased SYDE1 expression is associated with IUGR. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Diferenciação Celular/genética , Movimento Celular/genética , Proteínas Ativadoras de GTPase/genética , Proteínas de Membrana/genética , Placenta/metabolismo , Placentação/genética , Animais , Proteínas de Ligação a DNA , Feminino , Humanos , Camundongos , Proteínas Nucleares/genética , Gravidez , Sistema Renina-Angiotensina , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Trofoblastos/citologiaRESUMO
During human pregnancy, immune tolerance of the fetal semiallograft occurs in the presence of abundant maternal leukocytes. At the implantation site, macrophages comprise approximately 20% of the leukocyte population and act as primary mediators of tissue remodeling. Decidual macrophages display a balance between anti-inflammatory and proinflammatory phenotypes. However, a shift to an M1 subtype is reported in preeclampsia. Granulocyte-macrophage colony-stimulating-factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are major differentiating factors that mediate M1 and M2 polarization, respectively. Previously, we observed the following: i) the preeclamptic decidua contains an excess of both macrophages and GM-CSF, ii) the preeclampsia-associated proinflammatory cytokines, IL-1ß and tumor necrosis factor-α, markedly enhance GM-CSF and M-CSF expression in cultured leukocyte-free first-trimester decidual cells (FTDCs), iii) FTDC-secreted GM-CSF polarizes macrophages toward an M1 subtype. The microenvironment is a key determinant of macrophage phenotype. Thus, we examined proinflammatory stimulation of FTDC-secreted M-CSF and its role in macrophage development. Immunofluorescence staining demonstrated elevated M-CSF-positive decidual cell numbers in preeclamptic decidua. In FTDCs, IL-1ß and tumor necrosis factor-α signal through the NF-κB pathway to induce M-CSF production, which does the following: i) enhances differentiation of and elevates CD163 expression in macrophages, ii) increases macrophage phagocytic capacity, and iii) inhibits signal-regulatory protein α expression by macrophages. These findings suggest that FTDC-secreted M-CSF modulates the decidual immune balance by inducing M2 macrophage polarization and phagocytic capacity in response to proinflammatory stimuli.
Assuntos
Decídua/imunologia , Fator Estimulador de Colônias de Macrófagos/fisiologia , Pré-Eclâmpsia/imunologia , Antígenos de Diferenciação/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Decídua/metabolismo , Feminino , Humanos , Interleucina-1beta/fisiologia , Fator Estimulador de Colônias de Macrófagos/biossíntese , Fator Estimulador de Colônias de Macrófagos/metabolismo , NF-kappa B/metabolismo , Fagocitose/imunologia , Gravidez , Primeiro Trimestre da Gravidez , Receptores Imunológicos/metabolismo , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
A high concentration of copper is a hazardous element to organisms and human health. Although various strategies have been reported for the sensitive detection of copper, a facile and rapid detection of aqueous copper has seldom been addressed to date. Here, we present an easy and accessible colorimetric method to detect Cu2+ using the redispersion of cysteamine-modified gold nanoparticles (CA-AuNPs). Initially, CA caused the aggregation of AuNPs due to the electrostatic interaction and aggregated AuNPs can be regenerated in basic medium. The subsequent addition of Cu2+ to the CA-AuNP dispersion could effectively trigger the aggregation of CA-AuNPs, resulting from the coordination reactivity between the deprotonated CA and Cu2+. This strategy resulted in a detection limit (LOD) of 1.52 µM in drinking water, which is below the U.S. Environmental Protection Agency permissible limit (20 µM). To demonstrate the broad application of CA-AuNPs, we further applied this method to plasmonic immunoassays based on the competitive interaction of Cu2+ between CA-AuNPs and enzymes. The LOD of the Down syndrome biomarker hyperglycosylated human chorionic gonadotropin (H-hCG) was 0.125 mIU mL-1, which is better than that of commercial immunoassays. Importantly, the determination of H-hCG in serum indicates its applicability for the measurement of real samples. Our assay agrees well with the current immunoassay systems and thus it can easily be expanded to a more common sensing platform for different types of biotargets by changing the corresponding antibodies.
Assuntos
Colorimetria , Cobre/análise , Ouro , Imunoensaio , Nanopartículas Metálicas , Adulto , Técnicas Biossensoriais , Gonadotropina Coriônica/análise , Água Potável/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Limite de Detecção , Masculino , Gravidez , UrináliseRESUMO
AIM: The aim of this study was to explore the effects of a self-management intervention for middle-aged adults with knee osteoarthritis. BACKGROUND: Knee osteoarthritis is a common cause of lower limb disability in middle-aged and older adults. Use of self-management interventions that apply the self-regulation theory have not been reported for patients with knee osteoarthritis. DESIGN: A quasi-experimental design was applied. METHODS: Knee osteoarthritis patients were recruited from two medical centres in northern Taiwan by convenience sampling between July 2013-May 2014. We developed a self-management intervention programme for knee osteoarthritis; participants began an individualized programme 4 weeks after recruitment. Effectiveness of the intervention was evaluated using the Knee Injury and Osteoarthritis Outcome Score, Health Care Questionnaire and the Short-Form Health Survey. A generalized estimating equation compared assessment scores for 105 participants after the intervention (10 and 18 weeks) with scores at 4 weeks. RESULTS: Knee symptoms and physical function scores significantly improved and quality-of-life scores significantly increased while body mass index, unplanned medical consultations and doses of pain medication significantly decreased at 10 and 18 weeks compared with 4 weeks. After adjusting for the effect of time- and significant-related factors, knee symptoms and physical function, body mass index and quality of life significantly improved at 10 and 18 weeks compared with 4 weeks. CONCLUSIONS: The self-management intervention based on self-regulation theory, improved participants' symptoms and functions of knee osteoarthritis, overall health and quality of life. Offering self-management interventions in clinical practice can be beneficial for patients with knee osteoarthritis.
Assuntos
Osteoartrite do Joelho/enfermagem , Autogestão , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor , Qualidade de Vida , TaiwanRESUMO
Human trophoblast invasion of decidualized endometrium is essential for placentation and is tightly regulated and involves trophoblast-decidual cell interaction. High temperature requirement A4 (HtrA4) is a secreted serine protease highly expressed in the invasive extravillous trophoblasts that invade decidua. In contrast, both HtrA1 and HtrA3 have been shown to inhibit trophoblast invasion. Here we provide evidence that decidua-secreted HtrA1 and HtrA3 antagonize HtrA4-mediated trophoblast invasion. We demonstrated that HtrA1 and HtrA3 interact with and degrade HtrA4 and thereby inhibit trophoblast-like JAR cell invasion. Specifically, HtrA1 and HtrA3 expression is up-regulated under decidualization conditions in endometrial stromal and epithelial cells, T-HESCs and Ishikawa cells, respectively. Conditioned media from these two cell lines after decidualization treatment suppress HtrA4-expressing JAR cell invasion in an HtrA1- or HtrA3-dependent manner. Co-culture of the HtrA4-expressing JAR cells with decidualization stimuli-treated T-HESC or Ishikawa monolayer also impairs JAR cell invasion, which can be reversed by HtrA1 or HtrA3 knockdown, supporting that HtrA1 and HtrA3 are crucial for trophoblast-decidual cell interaction in the control of trophoblast invasion. Our study reveals a novel regulatory mechanism of trophoblast invasion through physical and functional interaction between HtrA family members.
Assuntos
Serina Endopeptidases/metabolismo , Serina Proteases/metabolismo , Trofoblastos/enzimologia , Feminino , Células HEK293 , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Trofoblastos/citologiaRESUMO
We studied the smooth muscle cell differentiation capability of human placental multipotent mesenchymal stromal cells (hPMSCs) and identified how endothelial cells recruit hPMSCs participating in vessel formation. hPMSCs from term placentas were induced to differentiate into smooth muscle cells under induction conditions and different matrix substrates. We assessed endothelial cells from umbilical veins for platelet-derived growth factor (PDGF)-BB expression and to induce hPMSC PDGFR-beta and STAT3 activation. Endothelial cells were co-cultured with hPMSCs for in vitro angiogenesis. Cell differentiation ability was then further assessed by mouse placenta transplantation assay. hPMSCs can differentiate into smooth muscle cells; collagen type I and IV or laminin support this differentiation. Endothelial cells expressed significant levels of PDGF-BB and activated STAT3 transcriptional activity in hPMSCs. Endothelial cell-conditioned medium induced hPMSC migration, which was inhibited by STAT3 small interfering RNA transfection or by pretreatement with PDGFR-beta-blocking antibody but not by PDGFR-alpha-blocking antibody or isotype immunoglobulin G (IgG; P < 0.001). hPMSCs can incorporate into endothelial cells with tube formation and promote endothelial cells, forming capillary-like networks than endothelial cells alone (tube lengths: 12 024.1 ± 960.1 vs. 9404.2 ± 584.7 pixels; P < 0.001). Capillary-like networks were significantly reduced by hPMSCs pretreated with PDGFR-beta-blocking antibody but not by PDGFR-alpha-blocking antibody or isotype IgG (P < 0.001). Transplantation of hPMSCs into mouse placentas revealed incorporation of the hPMSCs into vessel walls, which expressed alpha-smooth muscle actin, calponin, and smooth muscle myosin (heavy chain) in vivo. In conclusion, endothelial cell-hPMSC interactions occur during vessel development of placenta. Placental endothelial cell-derived PDGF-BB recruits hPMSCs involved in vascular development via PDGFR-beta/STAT3 activation.
Assuntos
Células-Tronco Mesenquimais/fisiologia , Neovascularização Fisiológica/fisiologia , Placenta/citologia , Células-Tronco Pluripotentes/fisiologia , Proteínas Proto-Oncogênicas c-sis/fisiologia , Fator de Transcrição STAT3/fisiologia , Animais , Becaplermina , Diferenciação Celular , Células Endoteliais/fisiologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Músculo Liso Vascular/citologia , Placenta/irrigação sanguínea , Placenta/transplante , Gravidez , Proteínas Proto-Oncogênicas c-sis/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , TransfecçãoRESUMO
The thyroid hormone, 3,3,5-triiodo-L-thyronine (T3), modulates several physiological processes, including cellular growth, differentiation, metabolism, inflammation and proliferation, via interactions with thyroid hormone response elements (TREs) in the regulatory regions of target genes. Infection and inflammation are critical processes in placental development and pregnancy-related diseases. In particular, infection is the leading cause of neonatal mortality and morbidity worldwide. However, to date, no successful approach has been developed for the effective diagnosis of infection in preterm infants. Pre-eclampsia (PE) is a serious disorder that adversely affects ~5% of human pregnancies. Recent studies identified a multiprotein complex, the inflammasome, including the Nod-like receptor (NLR) family of cytosolic pattern recognition receptors, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1, which plays a vital role in the placenta. The thyroid hormone modulates inflammation processes and is additionally implicated in placental development and disease. Therefore, elucidation of thyroid hormone receptor-regulated inflammation-related molecules, and their underlying mechanisms in placenta, should facilitate the identification of novel predictive and therapeutic targets for placental disorders. This review provides a detailed summary of current knowledge with respect to identification of useful biomarkers and their physiological significance in placenta.
Assuntos
Placenta/metabolismo , Hormônios Tireóideos/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Inflamação , Doenças Placentárias/metabolismo , Doenças Placentárias/patologia , Placentação , Gravidez , Receptores dos Hormônios Tireóideos/metabolismoRESUMO
BACKGROUND: The thyroid hormone, 3, 3', 5-triiodo-L-thyronine (T3), has been shown to modulate cellular processes via interactions with thyroid hormone receptors (TRs), but the secretory proteins that are regulated to exert these effects remain to be characterized. Brain-specific serine protease 4 (BSSP4), a member of the human serine protease family, participates in extracellular matrix remodeling. However, the physiological role and underlying mechanism of T3-mediated regulation of BSSP4 in hepatocellular carcinogenesis are yet to be established. METHODS: The thyroid hormone response element was identified by reporter and chromatin immunoprecipitation assays. The cell motility was analyzed via transwell and SCID mice. The BSSP4 expression in clinical specimens was examined by Western blot and quantitative reverse transcription polymerase chain reaction. RESULTS: Upregulation of BSSP4 at mRNA and protein levels after T3 stimulation is a time- and dose-dependent manner in hepatoma cell lines. Additionally, the regulatory region of the BSSP4 promoter stimulated by T3 was identified at positions -609/-594. BSSP4 overexpression enhanced tumor cell migration and invasion, both in vitro and in vivo. Subsequently, BSSP4-induced migration occurs through the ERK 1/2-C/EBPß-VEGF cascade, similar to that observed in HepG2-TRα1 and J7-TRα1 cells. BSSP4 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively associated with TRα1 and VEGF to a significant extent. Importantly, a mild association between BSSP4 expression and distant metastasis was observed. CONCLUSIONS: Our findings collectively support a potential role of T3 in cancer cell progression through regulation of the BSSP4 protease via the ERK 1/2-C/EBPß-VEGF cascade. BSSP4 may thus be effectively utilized as a novel marker and anti-cancer therapeutic target in HCC.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Serina Endopeptidases/genética , Hormônios Tireóideos/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Invasividade Neoplásica/genética , Regiões Promotoras Genéticas , Receptores dos Hormônios Tireóideos/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The role of human placental multipotent mesenchymal stromal cells (hPMSCs) in placental inflammation is unknown. We hypothesize that hPMSCs are involved in the early phases of placental infection. hPMSCs were isolated from term placentas and neutrophils from peripheral blood. The expression of toll-like receptors (TLRs) and cytokines by hPMSCs was determined by RT-PCR, flow cytometry and enzyme-linked immunosorbent assay. The effect of conditioned medium of hPMSCs with or without lipopolysaccharide (LPS) pretreatment on neutrophil functions: migration, apoptosis and production of reactive oxygen species (ROS) was assessed by flow cytometry and western blot. hPMSCs expressed TLR1, TLR3, TLR4, TLR6, TLR7 and TLR9. LPS stimulation increased the expression of TLR4 and the production of IL-6 and IL-8 by hPMSCs. Neutrophils exhibited chemotaxis to hPMSC-conditioned medium, which was inhibited by IL-8 depletion. Neutrophil CD11b activation was promoted by hPMSC-conditioned medium, which was further enhanced in media from hPMSCs pretreated with LPS. hPMSC-conditioned medium reduced neutrophil ROS production. Neutrophil phagocytosis was increased by LPS alone but not by hPMSC-conditioned medium with or without LPS stimulation. hPMSC-conditioned medium induced STAT3 activation in neutrophils, which was inhibited by neutralizing antibody to IL-6. hPMSC-conditioned medium rescued neutrophils from apoptosis, but this effect was significantly reduced in conditioned medium of hPMSCs with LPS pretreatment. Depletion of IL-6 from the conditioned medium further inhibited the anti-apoptotic effect on neutrophils. Our results demonstrate that hPMSCs can interact with peripheral blood neutrophils in response to inflammatory signals of the placenta. Cytokines produced by hPMSCs can induce neutrophil chemotaxis and reduce neutrophil apoptosis.