RESUMEN
BACKGROUND: Patients with abnormally invasive placenta (AIP) are at high risk of massive postpartum hemorrhage. Resuscitative endovascular balloon occlusion of the aorta (REBOA), as an adjunct therapeutic strategy for hemostasis, offers the obstetrician an alternative for treating patients with AIP. This study aimed to evaluate the role of REBOA in hemorrhage control in patients with AIP. METHODS: This was a historical cohort study with prospectively collected data between January 2014 to July 2021 at a single tertiary center. According to delivery management, 364 singleton pregnant AIP patients desiring uterus preservation were separated into two groups. The study group (balloon group, n = 278) underwent REBOA during cesarean section, whereas the reference group (n = 86) did not undergo REBOA. Surgical details and maternal outcomes were collected. The primary outcome was estimated blood loss and the rate of uterine preservation. RESULTS: A total of 278 (76.4%) participants experienced REBOA during cesarean section. The patients in the balloon group had a smaller blood loss during cesarean Sect. (1370.5 [752.0] ml vs. 3536.8 [1383.2] ml; P < .001) and had their uterus salvaged more often (264 [95.0%] vs. 23 [26.7%]; P < .001). These patients were also less likely to be admitted to the intensive care unit after delivery (168 [60.4%] vs. 67 [77.9%]; P = .003) and had a shorter operating time (96.3 [37.6] min vs. 160.6 [45.5] min; P < .001). The rate of neonatal intensive care unit admission (176 [63.3%] vs. 52 [60.4%]; P = .70) and total maternal medical costs ($4925.4 [1740.7] vs. $5083.2 [1705.1]; P = .13) did not differ between the two groups. CONCLUSIONS: As a robust hemorrhage-control technique, REBOA can reduce intraoperative hemorrhage in patients with AIP. The next step is identifying associated risk factors and defining REBOA inclusion criteria to identify the subgroups of AIP patients who may benefit more.
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Oclusión con Balón , Hemorragia Posparto , Recién Nacido , Humanos , Embarazo , Femenino , Estudios de Cohortes , Cesárea/efectos adversos , Aorta , Hemorragia Posparto/prevención & control , Hemorragia Posparto/etiología , Placenta , Resucitación/métodos , Oclusión con Balón/métodos , Estudios RetrospectivosRESUMEN
Preeclampsia (PE), a pregnancy disorder that affects 5-7% of pregnant women, is among the primary causes for maternal and perinatal mortality. PE is believed to be associated with insufficient invasion of villous and extravillous trophoblasts (EVTs), which hampers uterine spiral artery remodeling and finally induces PE. But the mechanism responsible for reduction of trophoblast invasion remains unclear. In this study, placental tissues taken from healthy donors and PE patients were used to evaluate the miR-326 expression; CCK8 and colony formation assays were used to confirm the effect of miR-326 on cell proliferation; transwell assay was used to demonstrate the effect of miR-326 on cell invasion capability; western blot was used to investigate the underlying mechanism; and luciferase assay was used to detect the effect of miR-326 on YAP/TAZ-mediated transcription activity. It was revealed the miR-326 expression was higher in placentas from PE patients than from healthy donors. After transfection of miR-326 mimics, trophoblast proliferation and invasion were impaired. Using TargetScan, we speculated that PAX8 was a target of miR-326, which was later confirmed by western blot. The YAP/TAZ expression was also downregulated after transfection with miR-326. Luciferase assay demonstrated that overexpression of miR-326 suppressed YAP/TAZ-mediated transcription activity by targeting PAX8. Overexpression of PAX8 could partly rescue miR-326-induced suppression of trophoblast proliferation and invasion. Taken together, our result indicated that miR-326 suppresses trophoblast growth, invasion, and migration by means of targeting PAX8 via the Hippo pathway.
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MicroARNs/fisiología , Factor de Transcripción PAX8/genética , Trofoblastos/fisiología , Adulto , Movimiento Celular/genética , Proliferación Celular/genética , Células Cultivadas , Regulación hacia Abajo/genética , Femenino , Regulación de la Expresión Génica , Vía de Señalización Hippo/fisiología , Humanos , EmbarazoRESUMEN
Our previous studies have shown that the Adipose-derived mesenchymal stem cells (ADSCs) can regulate metastasis and development of ovarian cancer. However, its specific mechanism has yet to be fully revealed. In this study, an RNA-seq approach was adopted to compare the differences in mRNA levels in ovarian cancer cells being given or not given ADSCs. The mRNA level of paired box 8 (PAX8) changed significantly and was confirmed as an important factor in tumour-inducing effect of ADSCs. In comparison with the ovarian cancer cells cultured in the common growth medium, those cultured in the medium supplemented with ADSCs showed a significant increase of the PAX8 level. Moreover, the cancer cell growth could be restricted, even in the ADSC-treated group (P < .05), by inhibiting PAX8. In addition, an overexpression of PAX8 could elevate the proliferation of ovarian cancer cells. Moreover, Co-IP assays in ovarian cancer cells revealed that an interaction existed between endogenous PAX8 and TAZ. And the PAX8 levels regulated the degradation of TAZ. The bioluminescence images captured in vivo manifested that the proliferation and the PAX8 expression level in ovarian cancers increased in the ADMSC-treated group, and the effect of ADSCs in promoting tumours was weakened through inhibiting PAX8. Our findings indicate that the PAX8 expression increment could contribute a role in promoting the ADSC-induced ovarian cancer cell proliferation through TAZ stability regulation.
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Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/química , Células Madre Mesenquimatosas/citología , Neoplasias Ováricas/patología , Factor de Transcripción PAX8/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Factor de Transcripción PAX8/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Preeclampsia (PE) is a specific obstetric disorder that may result in maternal and neonatal morbidity and mortality. Increasing evidence has been indicated that some candidate genes related to oxidative stress, such as glutamate-cysteine ligase, catalytic subunit (GCLC), glutamate-cysteine ligase, modifier subunit (GCLM), involve in the pathogenesis of PE. After the genetic contribution of GCLC rs17883901 polymorphism was analyzed by TaqMan allelic discrimination real-time PCR in 1001 PE patients and 1182 normal pregnant women, a case-control association analysis was performed. Although no statistical difference was found in genetic distribution of rs17883901 in GCLC between PE and control group (χ2 = 2.201, p = .333 by genotypic, χ2 = 0.524, p = .469, OR = 0.932, 95%CI = 0.771-1.128 by allelic), significant differences in the genotypic frequencies were investigated between mild PE group (χ2 = 6.999, p = .030) or late-onset PE group (χ2 = 6.197, p = .045) and control group. Furthermore, when dividing the mild PE patients, the late-onset PE patients and the controls into TT/CT + CC, TT + CT/CC, and TT/CC subgroups, we found statistical differences between mild PE and controls (TT/CT + CC:χ2 = 5.132, p = .023, OR = 2.948, 95%CI = 1.107-7.854; TT/CC:χ2 = 4.564, p = .033, OR = 2.793, 95%CI = 1.046-7.460) as well as late-onset PE and controls (TT/CT + CC:χ2 = 4.043, p = .044, OR = 2.248, 95%CI = 1.000-5.055). This is the first study to indicate GCLC rs17883901 polymorphism may be associated with a risk of mild PE and late-onset PE in Chinese Han women. However, additional well-designed studies with multi-ethnic and large-scale samples should be performed to validate our results.
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Glutamato-Cisteína Ligasa/genética , Polimorfismo de Nucleótido Simple , Preeclampsia/genética , Adulto , Pueblo Asiatico/genética , Pueblo Asiatico/estadística & datos numéricos , Estudios de Casos y Controles , China/epidemiología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Preeclampsia/etnología , Embarazo , Adulto JovenRESUMEN
We previously confirmed that Nuclear factor erythroid 2-related factor-2 (Nrf2) and heme oxygenase (HO-1) play synergistic roles in the pathogenesis of preeclampsia. To further explore the function of HO-1 in the pathogenesis of preeclampsia, we established oxidative stress models respectively with human first-trimester trophoblast/simian virus (HTR8/SVneo) and human umbilical vein endothelial cells (HUVECs) and then assessed the effect of HO-1 on the two cell lines in oxidative stress conditions. The cell oxidative stress models were incubated with Hemin (an inducer of HO-1), then, the HTR8/SVneo cells were transfected by ZO-1 small interfering RNA (siRNA). The HTR-8/SVneo invasive abilities were detected, and the tube formation abilities of HUVECs were measured. HO-1 and tight junction proteins zonula occludens-1 (ZO-1) and occludin in the cells were detected. In both the trophoblastic and HUVEC oxidative stress models, HO-1ãZO-1 and occludin were increased incubated with Hemin. Meanwhile, HTR-8/SVneo cells incubated with Hemin showed increased invasion function against the destruction of hydrogen peroxide (H2O2). Similarly, the tube formation ability of HUVECs incubated with Hemin was increased. The above-mentioned effects were disappeared after HTR-8/SVneo cells were transfected by ZO-1 siRNA. These results suggest that HO-1 protects the function of placental cells in oxidative stress via regulating ZO-1/occludin.
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Hemo-Oxigenasa 1/metabolismo , Ocludina/metabolismo , Estrés Oxidativo , Placenta/metabolismo , Proteína de la Zonula Occludens-1/metabolismo , Línea Celular , Activación Enzimática , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Placenta/citología , EmbarazoRESUMEN
Objective: To determine whether maternal plasma human placental lactogen (hPL) mRNA levels can predict abnormally invasive placenta. Study design: Sixty-eight singleton pregnant women with prior Cesarean deliveries were classified into three groups: 35 with normal placentation (control group); 21 with placenta previa alone (placenta previa group); 12 with placenta previa and placenta accreta (placenta accreta group). Maternal plasma hPL mRNA concentrations were measured by real-time reverse-transcription polymerase chain reaction Result: The multiple of the median (median, range) for hPL mRNA was significantly higher for the placenta accreta group (2.78, 1.09-4.56) than the control (1.00, 0.29-2.98) or placenta previa (1.12, 0.33-3.25) groups (Steel-Dwass test, p < .001 and p = .005, respectively), was not significantly different between the women with placenta accreta who underwent hysterectomies (2.96, 1.38-4.56) and the women whose deliveries did not result in hysterectomy (2.36, 1.09-3.25) in the placenta accreta group (Mann-Whitney U test, p = .372). Conclusion: hPL mRNA in maternal plasma may indicate abnormally invasive placenta but cannot predict whether abnormally invasive placenta will result in hysterectomy.
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Placenta Accreta/diagnóstico , Placenta Previa/diagnóstico , Lactógeno Placentario/sangre , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Histerectomía , Placenta Accreta/sangre , Placenta Accreta/cirugía , Placenta Previa/sangre , Placenta Previa/cirugía , Embarazo , Diagnóstico Prenatal , ARN MensajeroRESUMEN
OBJECTIVES: The purpose of this study was to investigate the expression of Filamin b in the placental placenta of patients with early or late onset pre-eclampsia (PE) and its potential effects on the pathophysiology of the disease. METHODS AND METHODS: Immunohistochemistry staining, western blot assays and real time PCR were used to detect the expression level of FLN-b. The expression levels of MMP-2, MMP-9 and ERK1/2 proteins from control and FLN-b-silenced JEG-3 cells were also detected by western blot and JEG-3 cell invasion. RESULTS: Compared with normal term pregnancies placentas, the FLN-b expression was significantly lower than that of women with PE, its level in late-onset PE is lower than in early-onset PE. In FLN-b-silenced JEG-3 cells, the protein levels of MMP-2, MMP-9 and phosphorylated ERK1/2 decreased markedly and the number of cells penetrating through the transwell chamber membrane is also greatly reduced. CONCLUSIONS: Down-regulation of FLN-b inhibits the ERK/MMP-2 and MMP-9 pathways, leading to trophoblastic invasion disorders in the PE placenta.
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Filaminas/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Metaloproteinasa 9 de la Matriz/metabolismo , Placenta , Preeclampsia/metabolismo , Adulto , Línea Celular Tumoral , Femenino , Filaminas/análisis , Filaminas/genética , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Placenta/química , Placenta/citología , Placenta/metabolismo , Embarazo , Trofoblastos/citología , Adulto JovenRESUMEN
Endometrial cancer is the most common gynaecological cancer, and its incidence is increasing. Obesity is a well-recognized risk factor for endometrial cancer, and the mechanisms by which adipose tissue influences tumour development remain controversial. In this study, we examined the high IL-6 level in the ADSCs supernatant following treatment of endometrial cancer cell CM. Then, the activation of STAT3, a major tumourigenic IL-6 effector, was examined in ADSCs CM treated endometrial cancer cells. Conditioned ADSC medium was used to stimulate endometrial cancer cell growth in vitro. Similar to IL-6, ADSC-conditioned medium significantly promoted endometrial cancer growth and invasion. Furthermore, siRNA-mediated STAT3 inhibition in endometrial cancer cells decreased the ADSC-mediated promotion of cell proliferation and invasion. In addition, a subcutaneous nude mouse model of endometrial cancer was established to monitor the tumour-promoting effect of ADSCs. ADSC-conditioned medium promoted tumour growth, and STAT3 inhibition attenuated this effect. Based on these data, ADSCs promote endometrial cancer progression by the STAT3 signalling pathway.
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Tejido Adiposo/citología , Neoplasias Endometriales/patología , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Células Madre/citología , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la NeoplasiaRESUMEN
AIM: Pre-eclampsia (PE) is a pregnancy complication characterized by new onset maternal hypertension and proteinuria. Its underlying mechanisms are unclear. This study investigated the relationship between progesterone and endoplasmic reticulum stress (ERS) associated apoptosis induced by interleukin (IL)-1ß via the glucose regulated protein 78 (GRP78)/protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP-homologous protein (CHOP) pathway in BeWo cells. METHODS: Venous blood and placental tissues were collected from PE patients, normal pregnancy and preterm delivery cases, respectively. Progesterone serum levels were detected by enzyme-linked immunosorbent assay and ERS-related protein expression in placentas was examined by immunohistochemistry, reverse transcriptase-polymerase chain reaction and Western blot. BeWo cells were stimulated by IL-1ß to induce ERS associated apoptosis in vitro. The apoptotic rate was measured by flow cytometry. The mechanism of progesterone acting on IL-1ß induced ERS associated apoptosis was investigated by reverse transcriptase-polymerase chain reaction, Western blot and PERK small interfering RNA, with RU486 used as a receptor inhibitor. RESULTS: PE patients exhibited decreased serum levels of progesterone and activated ERS and increased ERS-related protein expression. IL-1ß could induce ERS and associated cell apoptosis by activating the GRP78/PERK/CHOP signal pathway, which could be inhibited by progesterone. PERK could be upregulated and phosphorylation activated in ERS. The protective effects of progesterone could be attenuated by RU486. CONCLUSION: IL-1ß could induce ERS associated cell apoptosis by activating the GRP78/PERK/CHOP signal pathway in BeWo cells and may play an important role in PE occurrence. Progesterone levels were decreased in patients with PE and seemed to have a protective effect by inhibiting ERS associated cell apoptosis.
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Apoptosis , Estrés del Retículo Endoplásmico , Proteínas de Choque Térmico/metabolismo , Interleucina-1beta/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Progesterona/sangre , Transducción de Señal , Factor de Transcripción CHOP/metabolismo , eIF-2 Quinasa/metabolismo , Adulto , Línea Celular , Chaperón BiP del Retículo Endoplásmico , Femenino , Humanos , Placenta/citología , Preeclampsia/sangre , EmbarazoRESUMEN
OBJECTIVE: To investigate the expression of advanced glycation end products (AGEs) and the receptor for AGE (RAGEs) in maternal blood, umbilical blood and placental tissues in women with severe preeclampsia (sPE) as well as any association with inflammatory processes. METHODS: The expressions of AGEs, RAGE, tumor necrosis factor-alpha (TNF)-α and vascular cell adhesion molecule-1 (VCAM)-1 in placental tissues were measured using immunohistochemistry. The levels of AGEs, RAGE, TNF-α and VCAM-1 in maternal blood, umbilical blood and placental extracts were assessed using enzyme-linked immunosorbent assays. Placental RAGE, TNF-α and VCAM-1 mRNA expression levels were determined by PCR. Placental AGEs, RAGE, TNF-α and VCAM-1 protein levels were determined by western blotting. RESULTS: The levels of AGEs, TNF-α and VCAM-1 in the maternal tissues and umbilical blood were significantly higher in the sPE group than in the normal pregnancy (NP) controls (p < 0.05). The serum level of sRAGE in the umbilical blood was lower in the sPE group than in the NP controls (p < 0.05), while sRAGE was higher in the maternal blood of sPE than in the NP (p < 0.05). The maternal serum levels of AGEs were positively correlated with that of TNF-α and VCAM-1 in the maternal blood. There were no correlations between the levels of RAGE, TNF-α or VCAM-1 in maternal blood or umbilical serum. There were no correlations between the levels of sRAGE and TNF-α or VCAM-1 in maternal blood or umbilical serum. The levels of AGEs were positively correlated with those of TNF-α and VCAM-1 in placental lysates. CONCLUSION: AGEs and RAGE appear to act as important mediators in regulating the inflammatory pathways of preeclampsia.
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Sangre Fetal/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Preeclampsia/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Adulto , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inflamación/metabolismo , Placenta/metabolismo , Preeclampsia/sangre , Embarazo , Factor de Necrosis Tumoral alfa/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
BACKGROUND: This study measured the serum levels of complement component (C)3a and C5a and the placental expressions of C3a receptor (R) and C5aR to determine a potential correlation with circulating angiotensin II type 1 (AT1) receptor agonistic autoantibody (AT1-AA) in severe pre-eclampsia. METHODS: A total of 118 women were recruited and divided into 2 groups: the control group (normotensive preterm pregnancies, n = 66) and severe pre-eclampsia group (n = 52). Levels of C3a, C5a and AT1-AA in serum were measured by enzyme-linked immunosorbent assay and C3aR and C5aR in placenta by Western blotting. RESULTS: Levels of C3a, C5a and AT1-AA in serum from the severe pre-eclampsia group were significantly higher than in controls (p < 0.05). Placental expression of C3aR and C5aR in the pre-eclampsia group was lower than that in controls (p < 0.05). There were significant positive correlations between levels of C3a, C5a and AT1-AA in serum from the pre-eclampsia group (p < 0.05). In contrast, there was no correlation between C3aR and C5aR in the placenta and AT1-AA in serum in the pre-eclampsia group (p > 0.05). CONCLUSION: Increased C3a, C5a and AT1-AA in the serum provide indirect evidence that AT1-AA-mediated activation contributes to activate complement, which is a key mechanism underlying the pathogenesis of severe pre-eclampsia.
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Autoanticuerpos/sangre , Placenta/metabolismo , Preeclampsia/inmunología , Preeclampsia/metabolismo , Receptor de Anafilatoxina C5a/metabolismo , Receptor de Angiotensina Tipo 1/inmunología , Receptores de Complemento/metabolismo , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Preeclampsia/sangre , Embarazo , Receptor de Anafilatoxina C5a/sangre , Receptores de Complemento/sangreRESUMEN
BACKGROUND: Previous studies have shown that oxidative stress is an important factor in preeclampsia (PE). Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor-2 (Nrf2) are protective proteins that are involved in combating oxidative stress in the body. Nrf2 is also an essential upstream transcription factor regulating HO-1. This study was aimed at exploring the physiological roles of HO-1 and Nrf2 in PE. METHODS: Serum and placenta were collected from 30 patients who presented with severe PE and 30 healthy pregnant females. HO-1 and Nrf2 levels in placenta were measured. Following stimulation of the HTR-8/SVneo cell line with tert-butylhydroquinone (tBHQ), an Nrf2 activator, nuclear Nrf2 protein and HO-1 mRNA levels were determined. RESULTS: Compared with the healthy pregnancy group, HO-1 protein and mRNA levels were increased in placental samples obtained from the severe PE group (p < 0.01, p < 0.05). Similar increases were also observed for Nrf2 protein levels (p < 0.01). Nuclear Nrf2 protein and HO-1 mRNA levels were both increased in the HTR-8/SVneo cell line following stimulation with tBHQ (p < 0.05). CONCLUSION: Patients with severe PE may be protected against oxidative injury following an elevation in HO-1 and Nrf2 levels. Nrf2 is likely to have a synergistic effect on HO-1 in PE.
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Hemo-Oxigenasa 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/fisiología , Placenta/metabolismo , Preeclampsia/metabolismo , Femenino , Humanos , Placenta/fisiopatología , Preeclampsia/fisiopatología , EmbarazoRESUMEN
BACKGROUND: Preeclampsia (PE) is associated with oxidative stress in the maternal circulation and placenta. This study aimed to determine if inhibition of lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) gives protection against oxidative stress-mediated trophoblast dysfunction. METHODS: Plasma and placenta samples were obtained from 106 women with PE and 106 women with normal pregnancy (NP). Oxidized low-density lipoprotein (oxLDL) and soluble LOX-1 levels were determined by enzyme-linked immunoassay. Placental LOX-1 expression was determined by western blotting. Trophoblasts were subjected to hypoxia and treated with pooled plasma from patients with PE. Expression levels of placenta growth factor (PIGF) and the soluble form of the PIGF receptor (sFlt-1) in trophoblasts were determined. RESULTS: Plasma concentrations of oxLDL and sLOX-1 were significantly over-expressed and LOX-1 protein expression in the placenta was significantly increased in PE patients compared with matched NP controls (both p < 0.05). Exposure of trophoblasts to hypoxia and pooled PE plasma induced overexpression of sFlt-1 and downregulation of PIGF. These effects were inhibited by the LOX-1 inhibitor TS20. CONCLUSION: LOX-1 accumulation may contribute to the pathogenesis of PE by promoting sFlt-1 production in trophoblasts, suggesting that oxidative stress may be an important mediator regulating angiogenic pathways in trophoblasts.
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Lipoproteínas LDL/metabolismo , Estrés Oxidativo/fisiología , Placenta/metabolismo , Preeclampsia/metabolismo , Proteínas Gestacionales/metabolismo , Receptores Depuradores de Clase E/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto , Femenino , Humanos , Lipoproteínas LDL/sangre , Factor de Crecimiento Placentario , Preeclampsia/sangre , Embarazo , Proteínas Gestacionales/efectos de los fármacos , Receptores Depuradores de Clase E/antagonistas & inhibidores , Receptores Depuradores de Clase E/sangre , Trofoblastos/metabolismo , Trofoblastos/patología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the correlation of the expressions of advanced glycation end products (AGE) and the receptor for advanced glycation end products (RAGE) in serum and placenta with the pathogenesis of preeclampsia. METHODS: From December 2013 to June 2014, 32 women with severe preeclampsia who received cesarean section in the Affiliated Hospital of Qingdao University were recruited in the study, defined as the severe preeclampsia group. 30 healthy pregnant women who received cesarean section in the same hospital were recruited as the control group. ELISA was used to measure the maternal serum AGE, soluble receptor for advanced glycation end products (sRAGE) and tumor necrosis factor-α (TNF-α) in these women. Furthermore, ELISA was also used to measure AGE and TNF-α in the placenta. The localizations of AGE and RAGE protein in placentas were detected by immunohistochemical SP method. RAGE and TNF-α mRNA expression in placentas were measured by real-time quantitative PCR. AGE, RAGE and TNF-α protein expression in placentas were measured by western blot, respectively. RESULTS: (1) The serum levels of AGE, sRAGE and TNF-α in the severe preeclampsia group were (538 ± 75), (367 ± 86) and (322 ± 40) ng/L, respectively. They were significantly higher than those in the control group [(454 ± 50), (286 ± 35) and (270 ± 35) ng/L, respectively] (P < 0.05). The levels of AGE showed positive correlation with the levels of TNF-α (r = 0.588, P < 0.05), while the levels of sRAGE showed no correlation with TNF-α (r = -0.041, P > 0.05). (2) In the severe preeclampsia group, the levels of AGE and TNF-α in placentas were (500 ± 82) and (334 ± 57) ng/L, which were higher than those in the control group [(431 ± 74) and (263 ± 46) ng/L, respectively] (P < 0.05). The levels of AGE showed positive correlation with the levels of TNF-É (r = 0.406, P < 0.05). (3) AGE and RAGE protein mainly located in the syncytiotrophoblasts, macrophages and vascular endothelial cells in the placentas of the two groups. AGE expressed mainly in the cytoplasm, and RAGE expressed in the cytoplasm and cell membranes. (4) RAGE and TNF-α mRNA expression in the placentas of the severe preeclampsia group were 12.6 ± 4.6 and 10.4 ± 2.4, which were significantly higher than those in the control group (0.9 ± 0.4 and 3.5 ± 0.9, P < 0.01). (5) The expressions of AGE, RAGE and TNF-α protein in placentas of the severe preeclampsia group were 0.68 ± 0.06, 0.82 ± 0.08 and 0.76 ± 0.08. All were significantly higher than those of the control group (0.46 ± 0.05, 0.42 ± 0.09 and 0.52 ± 0.07; P < 0.01). CONCLUSIONS: The levels of AGE and RAGE in serum and placentas elevated in the severe preeclampsia group, and the expression of TNF-α also elevated. These indicated that AGE and RAGE might be involved in the systemic inflammatory response and local inflammatory response in placentas, and then caused the preeclampsia.
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Productos Finales de Glicación Avanzada/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Western Blotting , Estudios de Casos y Controles , Células Endoteliales , Ensayo de Inmunoadsorción Enzimática , Femenino , Productos Finales de Glicación Avanzada/sangre , Humanos , Macrófagos , Placenta/irrigación sanguínea , Preeclampsia/sangre , Preeclampsia/patología , Embarazo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor para Productos Finales de Glicación Avanzada/sangre , Índice de Severidad de la Enfermedad , Trofoblastos , Factor de Necrosis Tumoral alfaRESUMEN
In a prior study, our group found that chorionic villus-derived mesenchymal stem cells (CV-MSCs) were capable of promoting trophoblast proliferative and invasive activity. The mechanistic basis for this activity, however, has yet to be clarified. As such, an RNA-Seq analysis was conducted using trophoblasts that were treated with or without CV-MSC-conditioned media. Of the differentially expressed genes identified when comparing these two groups of cells, 23 proliferation-associated genes were identified and knocked down to test their functional roles in trophoblasts. These analyses revealed that inhibiting neuregulin 1 (NRG1) expression was sufficient to suppress proliferation and induce cell cycle arrest in trophoblasts. Placental samples from patients with preeclampsia exhibited significantly increased NRG1 expression relative to samples from healthy pregnancies. Following treatment with CV-MSC-conditioned media, NRG1 was upregulated in trophoblasts at the mRNA and protein levels. Relative to control trophoblasts, those in which NRG1 had been knocked down exhibited significantly impaired proliferation and DNA replication with the inactivation of the NF-κB signaling pathway. In contrast, overexpressing NRG1 yielded the opposite trophoblast phenotypes. Even in cells overexpressing NRG1, inhibition of NF-κB signaling was sufficient to significantly suppress trophoblast proliferation (P < 0.05). These results indicate that elevated NRG1 expression may play a role in the ability of CV-MSCs to induce proliferative activity in trophoblasts through the NF-κB signaling axis.
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Studies on ischemia/reperfusion (I/R) injury suggest that exogenous neural stem cells (NSCs) are ideal candidates for stem cell therapy reperfusion injury. However, NSCs are difficult to obtain owing to ethical limitations. In addition, the survival, differentiation, and proliferation rates of transplanted exogenous NSCs are low, which limit their clinical application. Our previous study showed that neuregulin1ß (NRG1ß) alleviated cerebral I/R injury in rats. In this study, we aimed to induce human umbilical cord mesenchymal stem cells into NSCs and investigate the improvement effect and mechanism of NSCs pretreated with 10 nM NRG1ß on PC12 cells injured by oxygen-glucose deprivation/reoxygenation (OGD/R). Our results found that 5 and 10 nM NRG1ß promoted the generation and proliferation of NSCs. Co-culture of NSCs and PC12 cells under condition of OGD/R showed that pretreatment of NSCs with NRG1ß improved the level of reactive oxygen species, malondialdehyde, glutathione, superoxide dismutase, nicotinamide adenine dinucleotide phosphate, and nuclear factor erythroid 2-related factor 2 (Nrf2) and mitochondrial damage in injured PC12 cells; these indexes are related to ferroptosis. Research has reported that p53 and solute carrier family 7 member 11 (SLC7A11) play vital roles in ferroptosis caused by cerebral I/R injury. Our data show that the expression of p53 was increased and the level of glutathione peroxidase 4 (GPX4) was decreased after RNA interference-mediated knockdown of SLC7A11 in PC12 cells, but this change was alleviated after co-culturing NSCs with damaged PC12 cells. These findings suggest that NSCs pretreated with NRG1ß exhibited neuroprotective effects on PC12 cells subjected to OGD/R through influencing the level of ferroptosis regulated by p53/SLC7A11/GPX4 pathway.
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OBJECTIVE: To research the correlation of the expressions of lipocalin-2 (LCN-2) and its receptor (NGALR) in serum and placenta with preeclampsia. METHODS: From Dec.2010 to Apr.2011, 64 women with preeclampsia who delivered in Affiliated Hospital of Qingdao University Medical College were recruited in the study, including 26 women with moderate preeclampsia (MPE group) and 38 women with severe preeclampsia (SPE group). Twenty-five healthy pregnant women were taken as control group. LCN-2 and NGALR mRNA and protein expression in placenta were measured by reverse transcription-PCR (RT-PCR) and western blot, respectively. RESULTS: (1) The serum levels of LCN-2 in MPE group and SPE group [(58 ± 20), (90 ± 18) µg/L] were significantly higher than that in control group [(19 ± 6) µg/L, P < 0.01]; the serum LCN-2 level in SPE group was significantly higher than that in MPE group (P < 0.01). (2) LCN-2 mRNA expression in placenta in MPE group and SPE group (0.55 ± 0.14, 0.61 ± 0.14) were both significantly higher than that in control group (0.28 ± 0.16, P < 0.01); LCN-2 protein expression in placenta of MPE group and SPE group (2.2 ± 0.4, 2.4 ± 0.5) were also significantly higher than that in control group (1.4 ± 0.4, P < 0.01), no significant difference was found between MPE group and SPE group (P > 0.05). (3) No significant difference was found in the expressions of NGALR mRNA in placenta among MPE group, SPE group and control group (0.46 ± 0.11, 0.46 ± 0.14, 0.45 ± 0.15, P > 0.05). (4) NGALR protein expressions in MPE group, SPE group and control group were 2.7 ± 0.8, 3.0 ± 0.9, and 2.7 ± 0.9, and there were no significant difference among these three groups (P > 0.05). (5) In preeclampsia, serum LCN-2 level significant associated with 24 hours total urinary protein and uric acid (r = 0.565, 0.476, P < 0.01). LCN-2 serum level were not associated with systolic pressure and diastolic pressure (P > 0.05); there were no association with the expressions LCN-2 mRNA and protein in placenta (P > 0.05). CONCLUSIONS: Serum LCN-2 level is closely related to the progress of preeclampsia. Increasing expression of LCN-2 in placenta may be a compensatory response to preeclampsia.
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Proteínas de Fase Aguda/metabolismo , Lipocalinas/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Fase Aguda/genética , Adulto , Presión Sanguínea , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lipocalina 2 , Lipocalinas/sangre , Lipocalinas/genética , Proteínas de Transporte de Catión Orgánico/genética , Preeclampsia/sangre , Preeclampsia/fisiopatología , Embarazo , Tercer Trimestre del Embarazo , Proteínas Proto-Oncogénicas/sangre , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Ácido Úrico/sangreRESUMEN
OBJECTIVE: To investigate the variance levels of plasma soluble leukocyte differentiation antigens CD40 (sCD40) and soluble CD40 ligand (sCD40 L) in preeclamptic patients with renal damage and its relationship. METHODS: A total of 63 pregnant women attended the Department of Obstetrics, Affiliated Hospital of Qingdao University Medical College between August 2008 and June 2010. In the present study included 28 pregnant women with mild preeclampsia and 35 patients with severe preeclampsia. Thirty matched normotensive pregnant women were enrolled in the study as the control group. Expression of sCD40 and sCD40 L were determined by ELISA. At the same time, the blood routine, C reaction protein (CRP), urine routine, 24 hours urine protein excretion, and serum uric acid (UA), creatinine (Cr), blood urea nitrogen (BUN) were measured. The correlation analysis was performed between the sCD40/sCD40 L and the blood biochemical indexes in 3 groups. RESULTS: (1) The median levels of CRP in severe preeclampsia (10.8 mg/L) and mild preeclampsia group (7.1 mg/L) are significantly higher than that of control group (3.3 mg/L, P < 0.05); The level of CRP in severe preeclampsia group was also higher than that of mild preeclampsia group (P < 0.05). The median gestational age at delivery in severe preeclampsia (32.5 weeks) was significantly less than that of mild preeclampsia group (37.2 weeks) and normal group (38.6 weeks, P < 0.05). However no significant differences were observed between mild preeclampsia group and normal group (P > 0.05). The platelet count in severe preeclampsia (132 × 109/L) was significantly less than those of mild preeclampsia group (212 × 109/L) and normal group (216 × 109L, P < 0.01), but no significant differences were observed in blood platelet amount between mild preeclampsia group and normal group (P > 0.05). There was no significant difference in hemoglobin level and white blood cell in three groups (P > 0.05). (2) The sCD40 plasma concentration in severe, mild preeclampsia and normal group was 133.6, 126.5 and 90.7 ng/L, respectively. The sCD40 L plasma concentrations were 12.5, 10.4 and 4.4 ng/L respectively in the 3 groups. 24 hours urinary protein quantitative was 4.5 g/d, 0.8 g/d and 0 in the 3 groups respectively. And the UA level was 486 µmol/L, 289 µmol/L and 162 µmol/L. In the above three groups, the monitoring indicators were significantly higher in women with severe preeclampsia group compared with mild preeclampsia and control groups (P < 0.01), and there were also higher in mild preeclampsia group than that in control groups (P < 0.01). The level of plasma Cr (89 µmol/L) and BUN (5.32 mmol/L) in severe preeclampsia group were higher than those of mild preeclampsia group (66 µmol/L and 4.49 mmol/L) and control group (57 µmol/L and 3.32 mmol/L, P < 0.05). There was no significant difference between mild preeclampsia group and normal group (P > 0.05). (3) The correlation analysis indicated that the level of sCD40 has a positive correlation with 24 hours urinary protein quantitative (r = 0.434, P < 0.05), also significant positive correlation (r = 0.536, 0.528, P < 0.01) between the level of sCD40 and UA or CRP in women with preeclampsia. There was no significant correlation between the level of sCD40 and systolic blood pressure, diastolic blood pressure, delivery gestational age, Cr, BUN, and platelet count (r = 0.135, 0.183, -0.133, 0.190, 0.167, -0.221, all P > 0.05). There were positive correlation between the level of sCD40 L and 24 hours urine protein excretion, either UA or CRP (r = 0.591, 0.445, 0.539, all P < 0.01). No significant correlation was found between sCD40 L and systolic blood pressure, diastolic blood pressure, delivery gestational age, Cr, BUN, and platelet count (r = 0.178, 0.212, -0.292, 0.144, 0.135, -0.273, all P > 0.05). There was significant positive correlation between plasma sCD40 and sCD40 L (r = 0.707, P < 0.01). There was no relationship between the level of sCD40, sCD40 L and the blood biochemical indexes in normotensive pregnant women (P > 0.05). CONCLUSIONS: The plasma concentrations of sCD40 and sCD40 L are significantly higher in pregnant women with preeclampsia compared with the control, which may be involved in the development of preeclampsia and contribute to the kidney damage. The variance levels of sCD40 and sCD40 L may be also related to the severity of preeclampsia.
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Antígenos CD40/sangre , Ligando de CD40/sangre , Riñón/fisiopatología , Preeclampsia/sangre , Adulto , Biomarcadores/sangre , Presión Sanguínea , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Edad Gestacional , Humanos , Preeclampsia/patología , Embarazo , Índice de Severidad de la Enfermedad , Ácido Úrico/sangre , Adulto JovenRESUMEN
OBJECTIVE: To investigate the correlation of the expressions of angiopoietin-2 (Ang-2) and angiopoietin-2 receptor (Tie-2) in serum and placenta with preeclampsia. METHODS: From May 2009 to April 2010, 62 women with preeclampsia who delivered in Affiliated Hospital of Qingdao University Medical College were recruited in the study, including 30 women with moderate preeclampsia (MPE group) and 32 women with severe preeclampsia (SPE group). Another 30 healthy pregnant women were taken as control group. ELISA was used to measure the serum Ang-2 in these women. Semiquantitative reverse transcription (RT)-PCR was used to investigate the expressions of Ang-2 mRNA and Tie-2 mRNA in placenta. Western blot was used to determine the expression of Ang-2 protein in placenta. RESULTS: (1) The serum concentrations of Ang-2 in MPE group and SPE group were (5.4 ± 1.8) µg/L and (5.1 ± 1.7) µg/L, respectively. Both were significantly lower than that in control group (16.2 ± 4.5) µg/L (P < 0.01). There was no significant difference between MPE group and SPE group (P > 0.05). (2) The expressions of Ang-2 mRNA in placenta of MPE group (2.1 ± 0.7) and SPE group (2.0 ± 0.6) were both significantly lower than that of control group (5.8 ± 0.8; P < 0.01). But there was no significant difference in Ang-2 mRNA expression between MPE group and SPE group (P > 0.05). (3) No significant difference was found in the expressions of Tie-2 mRNA in placenta among MPE group (1.33 ± 0.04), SPE group (1.35 ± 0.05) and control group (1.34 ± 0.04; P > 0.05). (4) The expressions of Ang-2 protein in placenta of MPE group (2.0 ± 0.8) and SPE group (2.0 ± 0.8) were both significantly lower than that of control group (5.7 ± 0.9; P < 0.01), while no significant difference was found between MPE group and SPE group (P > 0.05). (5) In MPE group and SPE group, the serum concentrations of Ang-2 were positively correlated with the levels of Ang-2 mRNA and Ang-2 protein in placenta (r = 0.651, 0.627; P < 0.01). CONCLUSIONS: Decreased expressions of Ang-2 mRNA and Ang-2 protein in placenta reduced serum concentration of Ang-2. Low expression of Ang-2 may be involved in the pathophysiological process of preeclampsia by affecting the formation of placenta in early pregnancy.
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Angiopoyetina 2/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Receptor TIE-2/metabolismo , Adulto , Angiopoyetina 2/sangre , Angiopoyetina 2/genética , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Preeclampsia/sangre , Preeclampsia/patología , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor TIE-2/sangre , Receptor TIE-2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Trophoblast dysfunction during pregnancy is fundamentally involved in preeclampsia. Several studies have revealed that human chorionic villous mesenchymal stem cells (CV-MSCs) could regulate trophoblasts function. RESULTS: To understand how human chorionic villous mesenchymal stem cells (CV-MSCs) regulate trophoblast function, we treated trophoblasts with CV-MSC supernatant under hypoxic conditions. Treatment markedly enhanced proliferation and invasion and augmented autophagy. Transcriptome and pathway analyses of trophoblasts before and after treatment revealed JAK2/STAT3 signalling as an upstream regulator. In addition, STAT3 mRNA and protein levels increased during CV-MSC treatment. Consistent with these findings, JAK2/STAT3 signalling inhibition reduced the autophagy, survival and invasion of trophoblasts, even in the presence of CV-MSCs, and blocking autophagy did not affect STAT3 activation in trophoblasts treated with CV-MSCs. Importantly, STAT3 overexpression increased autophagy levels in trophoblasts; thus, it positively regulated autophagy in hypoxic trophoblasts. Human placental explants also proved our findings by showing that STAT3 was activated and that LC3B-II levels were increased by CV-MSC treatment. CONCLUSION: In summary, our data suggest that CV-MSC-dependent JAK2/STAT3 signalling activation is a prerequisite for autophagy upregulation in trophoblasts.