scholarly journals Pregnancy-Induced High Plasma Levels of Soluble Endoglin in Mice Lead to Preeclampsia Symptoms and Placental Abnormalities

2020 ◽  
Vol 22 (1) ◽  
pp. 165
Author(s):  
Lucía Pérez-Roque ◽  
Elena Núñez-Gómez ◽  
Alicia Rodríguez-Barbero ◽  
Carmelo Bernabéu ◽  
José M. López-Novoa ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Ex Vivo ◽  
Clinical Manifestations ◽  
High Plasma ◽  
Trophoblast Invasion ◽  
Future Research ◽  
Soluble Factors ◽  
Human Trophoblast ◽  
Soluble Endoglin ◽  
Pregnant Mice

Preeclampsia is a pregnancy-specific disease of high prevalence characterized by the onset of hypertension, among other maternal or fetal signs. Its etiopathogenesis remains elusive, but it is widely accepted that abnormal placentation results in the release of soluble factors that cause the clinical manifestations of the disease. An increased level of soluble endoglin (sEng) in plasma has been proposed to be an early diagnostic and prognostic biomarker of this disease. A pathogenic function of sEng involving hypertension has also been reported in several animal models with high levels of plasma sEng not directly dependent on pregnancy. The aim of this work was to study the functional effect of high plasma levels of sEng in the pathophysiology of preeclampsia in a model of pregnant mice, in which the levels of sEng in the maternal blood during pregnancy replicate the conditions of human preeclampsia. Our results show that wild type pregnant mice carrying human sEng-expressing transgenic fetuses (fWT(hsEng+)) present high plasma levels of sEng with a timing profile similar to that of human preeclampsia. High plasma levels of human sEng (hsEng) are associated with hypertension, proteinuria, fetal growth restriction, and the release of soluble factors to maternal plasma. In addition, fWT(hsEng+) mice also present placental alterations comparable to those caused by the poor remodeling of the spiral arteries characteristic of preeclampsia. In vitro and ex vivo experiments, performed in a human trophoblast cell line and human placental explants, show that sEng interferes with trophoblast invasion and the associated pseudovasculogenesis, a process by which cytotrophoblasts switch from an epithelial to an endothelial phenotype, both events being related to remodeling of the spiral arteries. Our findings provide a novel and useful animal model for future research in preeclampsia and reveal a much more relevant role of sEng in preeclampsia than initially proposed.

New insights into the function of Cullin 3 in trophoblast invasion and migration

Reproduction ◽  
2015 ◽  
Vol 150 (2) ◽  
pp. 139-149 ◽  
Author(s):  
Qian Zhang ◽  
Song Yu ◽  
Xing Huang ◽  
Yi Tan ◽  
Cheng Zhu ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Trophoblast Invasion ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
Invasion And Migration ◽  
Cullin 3 ◽  
And Migration ◽  
F Box Protein ◽  
Extravillous Trophoblasts

Cullin 3 (CUL3), a scaffold protein, assembles a large number of ubiquitin ligase complexes, similar to Skp1-Cullin 1-F-box protein complex. Several genetic models have shown that CUL3 is crucial for early embryonic development. Nevertheless, the role of CUL3 in human trophoblast function remains unclear. In this study, immunostaining revealed that CUL3 was strongly expressed in the villous cytotrophoblasts, the trophoblast column, and the invasive extravillous trophoblasts. Silencing CUL3 significantly inhibited the outgrowth of villous explant ex vivo and decreased invasion and migration of trophoblast HTR8/SVneo cells. Furthermore, CUL3 siRNA decreased pro-MMP9 activity and increased the levels of TIMP1 and 2. We also found that the level of CUL3 in the placental villi from pre-eclamptic patients was significantly lower as compared to that from their gestational age-matched controls. Moreover, in the lentiviral-mediated placenta-specific CUL3 knockdown mice, lack of CUL3 resulted in less invasive trophoblast cells in the maternal decidua. Taken together, these results suggest an essential role for CUL3 in the invasion and migration of trophoblast cells, and dysregulation of its expression may be associated with the onset of pre-eclampsia.

PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development

2015 ◽  
Vol 309 (4) ◽  
pp. E357-E369 ◽  
Author(s):  
Vanessa Garnier ◽  
Wael Traboulsi ◽  
Aude Salomon ◽  
Sophie Brouillet ◽  
Thierry Fournier ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Trophoblast Cell ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Migration And Invasion ◽  
Placental Development ◽  
Human Trophoblast ◽  
Pparγ Agonist

PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants ( n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ+/− and PPARγ−/− mice. Major processes of placental development that are known to be controlled by PPARγ, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ−/− mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion.

The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

1992 ◽  
Vol 67 (02) ◽  
pp. 258-263 ◽  
Author(s):  
Raffaele De Caterina ◽  
Rosa Sicari ◽  
An Yan ◽  
Walter Bernini ◽  
Daniela Giannessi ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Plasma Levels ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Random Sequence ◽  
Antiplatelet Agent ◽  
Antiplatelet Drug ◽  
Double Blind

SummaryIndobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean ± S.D., 58.7 ± 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 ±3% for both treatments). At 12 h inhibition was 87 ± 6% for d-indobufen and 88 ± 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs. Maximum inhibitory effect on aggregation was seen in response to collagen 1.5 pg/ml (63 ± 44% for d-indobufen and 81 ± 22% for dl-indobufen) and arachidonic acid 0.5-2 mM (78 ± 34% for d-indobufen and 88 ± 24% for dl-indobufen) at 2 h after each administration. An effect of both treatments on platelet aggregation after 12 h was present only for adrenaline 2 μM (55 ± 41% for d-indobufen and 37 ± 54% for dl-indobufen), collagen 1.5 pg/ml (69 ± 30% for d-indobufen and 51 ± 61% for dl-indobufen), arachidonic acid 0.5-2 mM (56 ± 48% for d-indobufen and 35 ± 49% for dl-indobufen). The extent of inhibition of TX production and the extent of residual platelet aggregation were never significantly different between treatments. Bleeding time prolongation was similar in the two treatment groups without showing a pronounced and long lasting effect (from 7.0 ± 2.0 min to 10.0 ± 3.0 min at 2 h and 8.0 ± 2.0 min at 12 h for d-indobufen; from 6.0 ±1.0 min to 8.5 ± 2.0 min at 2 h and 8.0 ± 1.0 min at 12 h for dl-indobufen). These results demonstrate that the biological activity of dl-indobufen as an antiplatelet agent in vivo is totally accounted for by d-indobufen.

Repurposing N,N-Dimethylacetamide (DMA), a Pharmaceutical Excipient, as a Prototype Novel Anti-inflammatory Agent for the Prevention and/or Treatment of Preterm Birth

2018 ◽  
Vol 24 (9) ◽  
pp. 989-992 ◽  
Author(s):  
Samir Gorasiya ◽  
Juliet Mushi ◽  
Ryan Pekson ◽  
Sabesan Yoganathan ◽  
Sandra E. Reznik
Keyword(s):  
Preterm Birth ◽  
Ex Vivo ◽  
The United States ◽  
Occurrence Rate ◽  
Pharmaceutical Excipient ◽  
Ongoing Work ◽  
Exciting Line ◽  
Pregnant Mice

Background: Preterm birth (PTB), or birth that occurs before 37 weeks of gestation, accounts for the majority of perinatal morbidity and mortality. As of 2016, PTB has an occurrence rate of 9.6% in the United States and accounts for up to 18 percent of births worldwide. Inflammation has been identified as the most common cause of PTB, but effective pharmacotherapy has yet to be developed to prevent inflammation driven PTB. Our group has discovered that N,N-dimethylacetamide (DMA), a readily available solvent commonly used as a pharmaceutical excipient, rescues lipopolysaccharide (LPS)-induced timed pregnant mice from PTB. Methods: We have used in vivo, ex vivo and in vitro approaches to investigate this compound further. Results: Interestingly, we found that DMA suppresses cytokine secretion by inhibiting nuclear factor-kappa B (NF-κB). In ongoing work in this exciting line of investigation, we are currently investigating structural analogs of DMA, some of them novel, to optimize this approach focused on the inflammation associated with PTB. Conclusion: Successful development of pharmacotherapy for the prevention of PTB rests upon the pursuit of multiple strategies to solve this important clinical challenge.

Association of microRNA-125a with the clinical features, disease activity and inflammatory cytokines of juvenile-onset lupus patients

Lupus ◽  
2021 ◽  
pp. 096120332110103
Author(s):  
Eman Eissa ◽  
Botros Morcos ◽  
Rania Fawzy Mahmoud Abdelkawy ◽  
Hanan H Ahmed ◽  
Naglaa M Kholoussi
Keyword(s):  
Disease Activity ◽  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Plasma Levels ◽  
Clinical Manifestations ◽  
Juvenile Onset ◽  
Expression Levels ◽  
Ifn Γ ◽  
Chronic Autoimmune Disease ◽  
Normal Controls

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with marked variation in its clinical presentation. Juvenile-onset SLE (jSLE) exhibits an aggressive clinical phenotype and severe complications. Dysregulated expression of microRNAs (miRs) in immune cells from patients with SLE has been found. We aim to evaluate the association of miR-125a with the clinical and laboratory characteristics, disease activity and inflammatory cytokines of jSLE patients. Methods 60 jSLE patients and 25 normal controls were involved in the study. The expression pattern of miR-125a was determined in plasma of all subjects using qRT-PCR. In addition, plasma levels of IL-17 and IFN-γ were examined using ELISA. The correlation of miR-125a expression with the clinical manifestations and disease activity of jSLE patients was analyzed. Also, its association with the inflammatory cytokines was investigated in jSLE patients. Results Our findings showed that miR-125a expression levels were significantly reduced in jSLE patients compared to normal controls ( p < 0.01) and these expression levels differed based on the clinical variability of patients. In addition, plasma levels of IL-17 and IFN-γ in jSLE patients were significantly higher than healthy controls ( p < 0.01). Finally, miR-125a expression had significant negative associations with each of SLEDAI-2K ( p < 0.01), SLICC ( p < 0.01), ESR ( p < 0.05), proteinuria ( p < 0.01) and IL-17 levels ( p < 0.01) in jSLE patients. Conclusion Our findings postulate that miR-125a could act as a candidate therapeutic target for its possible regulation of inflammation in jSLE patients.

scholarly journals Effect of Processing on Fish Protein Antigenicity and Allergenicity

Foods ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 969
Author(s):  
Xingyi Jiang ◽  
Qinchun Rao
Keyword(s):  
Fish Species ◽  
Protein Denaturation ◽  
Ex Vivo ◽  
Protein Solubility ◽  
Future Research ◽  
Food Protein ◽  
In Vivo Evaluation ◽  
Fish Allergy

Fish allergy is a life-long food allergy whose prevalence is affected by many demographic factors. Currently, there is no cure for fish allergy, which can only be managed by strict avoidance of fish in the diet. According to the WHO/IUIS Allergen Nomenclature Sub-Committee, 12 fish proteins are recognized as allergens. Different processing (thermal and non-thermal) techniques are applied to fish and fishery products to reduce microorganisms, extend shelf life, and alter organoleptic/nutritional properties. In this concise review, the development of a consistent terminology for studying food protein immunogenicity, antigenicity, and allergenicity is proposed. It also summarizes that food processing may lead to a decrease, no change, or even increase in fish antigenicity and allergenicity due to the change of protein solubility, protein denaturation, and the modification of linear or conformational epitopes. Recent studies investigated the effect of processing on fish antigenicity/allergenicity and were mainly conducted on commonly consumed fish species and major fish allergens using in vitro methods. Future research areas such as novel fish species/allergens and ex vivo/in vivo evaluation methods would convey a comprehensive view of the relationship between processing and fish allergy.

scholarly journals ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia

2019 ◽  
Vol 316 (4) ◽  
pp. C481-C491 ◽  
Author(s):  
Yalan Xu ◽  
Lili Sui ◽  
Bintao Qiu ◽  
Xiuju Yin ◽  
Juntao Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Western Blotting ◽  
Underlying Mechanism ◽  
Trophoblast Invasion ◽  
Pathological Examination ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
Annexin A4 ◽  
Extravillous Cytotrophoblasts ◽  
Phosphoinositide 3 Kinase

The inadequate trophoblast invasion is associated with the development of preeclampsia (PE). Considering that annexin A4 (ANXA4) enhances tumor invasion, we aimed to explore the functional role of ANXA4 in trophoblast cells and to examine the underlying mechanism. ANXA4 expression in PE placentas was analyzed using immunohistochemistry and Western blotting. Cell proliferation, invasion, and apoptosis were determined using a MTT assay, Transwell assay, and flow cytometry, respectively. The expression levels of matrix metalloproteinase (MMP)-2, MMP-9, phosphoinositide 3-kinase (PI3K), Akt, phosphorylated (p)-Akt, and phosphorylated endothelial nitric oxide synthase (p-eNOS) were detected by Western blotting. Placentas were prepared for pathological examination using hematoxylin and eosin staining and apoptosis determination using the TUNEL method. Expression of ANXA4, PI3K, p-Akt and p-eNOS was downregulated in human PE placentas and PE placenta-derived extravillous cytotrophoblasts (EVCTs). Furthermore, ANXA4 overexpression promoted cell proliferation and invasion, inhibited cell apoptosis, and upregulated protein expression of PI3K, p-Akt, and p-eNOS in human trophoblast cells HTR-8/SVneo and JEG-3. By contrast, ANXA4 knockdown exerted the opposite effects. Furthermore, inhibition of the PI3K/Akt pathway by LY294002 abrogated the ANXA4 overexpression-mediated effects on trophoblast behavior. Furthermore, eNOS knockdown abrogated the ANXA4 overexpression-induced promotion of cell invasion and MMP2/9 expression. Additionally, in N-nitro-l-arginine methyl ester (l-NAME)-induced PE rats, ANXA4 overexpression alleviated PE progression, accompanied by an increase in expression of PI3K, p-Akt, and p-eNOS in rat placentas. Our findings demonstrate that ANXA4 expression is downregulated in PE. ANXA4 may promote trophoblast invasion via the PI3K/Akt/eNOS pathway.

scholarly journals Update on Atopic Dermatitis

2019 ◽  
Vol 32 (9) ◽  
pp. 606 ◽  
Author(s):  
Tiago Torres ◽  
Eduarda Osório Ferreira ◽  
Margarida Gonçalo ◽  
Pedro Mendes-Bastos ◽  
Manuela Selores ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Disease Severity ◽  
Clinical Manifestations ◽  
Skin Barrier ◽  
Future Research ◽  
Severe Atopic Dermatitis ◽  
Inadequate Response ◽  
Barrier Dysfunction ◽  
Therapeutic Goals ◽  
Global Health Issue

With an increasing prevalence during the past decades, atopic dermatitis has become a global health issue. A literature search following a targeted approach was undertaken to perform this non-systematic review, which intends to provide an overview of the epidemiology, pathophysiology, clinical features, comorbidities, and current therapies for the treatment of atopic dermatitis. In sum, this is a heterogeneous skin disorder associated with variable morphology, distribution, and disease course. Although not completely understood, its pathogenesis is complex and seems to result from a combination of genetic and environmental factors that induce skin barrier dysfunction, cutaneous and systemic immune dysregulation, skin microbiota dysbiosis, and a strong genetic influence. Diagnosis is based on specific criteria that consider patient and family history and clinical manifestations. Overall disease severity must be determined by evaluating both objective signs and subjective symptoms. Therapeutic goals require a multistep approach, focusing on reducing pruritus and establishing disease control. Patients should be advised on basic skin care and avoidance of triggers. Topical anti-inflammatory agents should be considered in disease flares or chronic/recurrent lesions. In case of inadequate response, phototherapy, systemic immunosuppressants and, more recently, dupilumab, should be added. Nevertheless, the treatment of moderate-to-severe atopic dermatitis remains challenging and novel, efficacious, safe and targeted treatments are urgently needed. In conclusion, although the last few years have seen important improvement in the understanding of the disease, future research in atopic dermatitis will continue exploring gene-environment interactions and how it affects pathophysiology, disease severity, and treatment outcomes.

Human trophoblast invasion and endothelial-like differentiation are regulated by O2 and TGF-ß1 by a fibronectin dependent pathway: Hypothesis of fibronectin role in preeclampsia

Placenta ◽  
2021 ◽  
Vol 112 ◽  
pp. e52
Author(s):  
Denisse Moreno ◽  
Felipe Gallardo ◽  
Valentina Pasten ◽  
Rodrigo Escalona ◽  
Pedro Leiva ◽  
...  
Keyword(s):  
Trophoblast Invasion ◽  
Human Trophoblast ◽  
Dependent Pathway

High Plasma Levels of 8-Methoxypsoralen following Bath Water Delivery in Dermatological Patients

2003 ◽  
Vol 16 (5) ◽  
pp. 305-312 ◽  
Author(s):  
U.P. Kappes ◽  
U. Barta ◽  
U. Merkel ◽  
A. Balogh ◽  
P. Elsner
Keyword(s):  
Plasma Levels ◽  
High Plasma ◽  
Water Delivery ◽  
Bath Water
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