Regulatory mechanism and research progress of ferroptosis in obstetrical and gynecological diseases

Ferroptosis is a novel type of regulated cell death driven by iron-dependent lipid peroxidation, which is distinguished from traditional types of programmed cell death, such as apoptosis, proptosis and necrosis et al. Impaired iron homeostasis, lipid peroxidation and antioxidants depletion are three hallmarks of ferroptosis. Over the past years, emerging studies support the notion that ferroptosis might be involved in the pathology of obstetrical and gynecological diseases, including preeclampsia (PE), endometriosis (EMs) and polycystic ovarian syndrome (PCOS). In the PE condition, the high sensitivity of trophoblasts towards ferroptosis has been found to potentially link to inflammation, suboptimal vascular remodeling and aberrant hemodynamics, which are three prominent pathophysiological features of PE. As for EMs, compromised ferroptosis of endometrial cells was associated with the formation ectopic lesions, whereas in the nearby lesions, the presence of ferroptosis was suggested to promote the progression of EMs, contributing to the relative clinical manifestations. Ferroptosis has been implicated a crucial role in the initiation of ovarian follicular atresia, which might help to manage ovulation in PCOS patients. Taken together, this review explored the basis of ferroptosis mechanisms and comprehensively summarized the latest discovery of roles of ferroptosis on PE, EMs and PCOS, gaining a deeper insight into the pathogenesis of these obstetrical and gynecological diseases and investigation of novel therapeutic interventions

Emerging roles of APLN and APELA in the physiology and pathology of the female reproductive system

APLN, APELA and their common receptor APLNR (composing the apelinergic axis) have been described in various species with extensive body distribution and multiple physiological functions. Recent studies have witnessed emerging intracellular cascades triggered by APLN and APELA which play crucial roles in female reproductive organs, including hypothalamus-pituitary-gonadal axis, ovary, oviduct, uterus and placenta. However, a comprehensive summary of APLN and APELA roles in physiology and pathology of female reproductive system has not been reported to date. In this review, we aim to concentrate on the general characteristics of APLN and APELA, as well as their specific physiological roles in female reproductive system. Meanwhile, the pathological contexts of apelinergic axis dysregulation in the obstetrics and gynecology are also summarized here, suggesting its potential prospect as a diagnostic biomarker and/or therapeutic intervention in the polycystic ovary syndrome, ovarian cancer, preeclampsia and gestational diabetes mellitus

The regulation of ovary and conceptus on the uterine natural killer cells during early pregnancy

Abstract Uterine natural killer (uNK) cells are short-lived, terminally differentiated and the most abundant lymphocytes in the uterus which play a crucial role in the spiral arteriole modification and establishment of successful pregnancy. Dysregulation of uNK cells has been linked to gestational implications such as recurrent pregnancy loss, preeclampsia and fetal growth retardation. There is evidence showing that progesterone and estrogen can regulate the recruitment, proliferation, differentiation and function of uNK cells via direct action on intracellular nuclear receptors or through intermediary cells in the uterus during early pregnancy. As the deepening of related research in this field, the role of conceptus in such regulation has received extensive attention, it utilizes endocrine signaling (hCG), juxtacrine signaling (HLA-C, HLA-E, HLA-G) and paracrine signaling (cytokines) to facilitate the activities of uNK cells. In addition, under the influence of ovarian hormones, conceptus can increase expression of PIBF and HLA-G molecules to reduce cytotoxicity of uNK cells and promote angiogenesis. In this review, we aim to concentrate on the novel findings of ovarian hormones in the regulation of uNK cells, emphasize the regulatory role of conceptus on uNK cells and highlight the proposed issues for future research in the field

Constituents leached by tomato seeds regulate the behavior of root-knot nematodes and their antifungal effects against seed-borne fungi

Germinating seeds can release diverse phytochemicals that repel, inhibit, or kill pathogens such as root-knot nematodes and seed-borne fungi. However, little is known about the composition of these phytochemicals and their effects on pathogens. In this study, we demonstrated that tomato seed exudates can attract the nematode Meloidogyne incognita using a dual-choice assay. Eighteen compounds were then isolated and identified from the exudates. Of these, esters (1-3), fatty acids (4-6), and phenolic acids (10-12) were proven to be the signaling molecules that facilitated the host-seeking process of second-stage juveniles (J2s) of nematodes, while alkaloids (17 and 18) disrupted J2s in locating their host. Furthermore, some phenolic acids and alkaloids showed antifungal effects against seed-borne fungi. In particular, ferulic acid (12) showed obvious activity against Aspergillus flavus (minimum inhibitory concentration (MIC), 32 μg/mL), while dihydrocapsaicin (17) showed noticeable activity against Fusarium oxysporum (MIC, 16 μg/mL). Overall, this study presents the first evidence that M. incognita can be attracted to or deterred by various compounds in seed exudates through identification of the structures of the compounds in the exudates and analysis of their effects on nematodes. Furthermore, some antifungal compounds were also found. The findings of this work suggest that seed exudates are new source for finding insights into the development of plant protective substances with nematocidal and antifungal effects

Relationship between bisphenol A exposure and attention-deficit/hyperactivity disorder: A case-control study for primary school children in Guangzhou, China

Bisphenol A (BPA) is an endocrine-disrupting chemical. Studies have shown that the exposure to BPA is associated with attention-deficit/hyperactivity disorder (ADHD) during adolescent development. However the direct clinical evidence is limited. To investigate the possible association between environmental BPA exposure and the altered behavior of children, a case-control study was conducted with children aged 6-12 years in Guangzhou, China. Two hundred fifteen children diagnosed with ADHD and 253 healthy children from Guangzhou were recruited as the case and control groups, respectively. Urinary BPA and 8-hydroxy-2'-deoxyguanosine (8-OHdG, a biomarker of oxidative DNA damage) concentrations were determined by high-performance liquid chromatography/tandem spectrometry. The results showed that concentrations of urinary SPA for the case group were significantly higher than those for the control group (3.44 vs 1.70 mu g/L; 4.63 vs 1.71 mu g/g Crt. p < .001). A stepwise increase in the odds ratios for ADHD was observed with the increasing quartiles of children's urinary BPA (first quartile: reference category; second quartile adjusted OR: 1.79, 95% CI: 0.95-3.37; third quartile adjusted OR: 7.44, 95% CI: 3.91-14.1; fourth quartile adjusted OR: 9.41, 95% CI: 4.91-18.1). When the BPA levels were stratified by gender, the odds of ADHD among boys and girls increased significantly with urinary BPA concentrations (adjusted OR: 4.58, 95% CI: 2.84-7.37; adjusted OR: 2.83, 95% CI: 1.17-6.84). Urinary 8-OHdG concentrations in the ADHD children were significantly higher than those in the control group. Furthermore, the linear regression analysis results indicated that a significant relationship existed between BPA exposure and 8-OHdG levels (R = 0.257, p < .001). Our findings provide direct evidence that childhood BPA exposure may be related to ADHD and 8-OHdG concentrations for children. Moreover, BPA exposure could increase the higher occurrence of ADHD for boy than for girls. (C) 2017 Elsevier Ltd. All rights reserved

Down-Regulation of Neuropathy Target Esterase in Preeclampsia Placenta Inhibits Human Trophoblast Cell Invasion via Modulating MMP-9 Levels

Background/Aims: Neuropathy target esterase (NTE, also known as neurotoxic esterase) is proven to deacylate phosphatidylcholine (PC) to glycerophosphocholine as a phospholipase B. Recently; studies showed that artificial phosphatidylserine/PC microvesicles can induce preeclampsia (PE)-like changes in pregnant mice. However, it is unclear whether NTE plays a key role in the pathology of PE, a pregnancy-related disease, which was characterized by deficient trophoblast invasion and reduced trophoblast-mediated remodeling of spiral arteries. The aim of this study was to investigate the expression pattern of NTE in the placenta from women with PE and normal pregnancy, and the molecular mechanism of NTE involved in the development of PE. Methods: NTE expression levels in placentas from 20 pregnant women with PE and 20 healthy pregnant women were detected using quantitative PCR and immunohistochemistry staining. The effect of NTE on trophoblast migration and invasion and the underlying mechanisms were examined in HTR-8/SVneo cell lines by transfection method. Results: NTE mRNA and protein expression levels were significantly decreased in preeclamptic placentas than normal control. Over-expression of NTE in HTR-8/SVneo cells significantly promoted trophoblast cells migration and invasion and was associated with increased MMP-9 levels. Conversely, shRNA-mediated down-regulation of NTE markedly inhibited the cell migration and invasion. In addition, silencing NTE reduced the MMP-9 activity and phosphorylated Erk1/2 and AKT levels. Conclusions: Our results suggest that the decreased NTE may contribute to the development of PE through impairing trophoblast invasion by down-regulating MMP-9 via the Erk1/2 and AKT signaling pathway

Transient {beta}2-adrenoceptor activation confers pregnancy loss by disrupting embryo spacing at implantation.

Pregnancy loss is a serious social and medical issue, with one important cause associated with aberrant embryo implantation during early pregnancy. However, whether and how the process of embryo implantation is affected by environmental factors such as stress-induced sympathetic activation remained elusive. Here we report an unexpected, transient effect of β(2)-adrenoreceptor (β(2)-AR) activation (day 4 postcoitus) in disrupting embryo spacing at implantation, leading to substantially increased midterm pregnancy loss. The abnormal embryo spacing could be prevented by pretreatment of β(2)-AR antagonist or genetic ablation of β-AR. Similar β(2)-AR activation at day 5 postcoitus, when implantation sites have been established, did not affect embryo spacing or pregnancy outcome, indicating that the adverse effect of β(2)-AR activation is limited to the preimplantation period before embryo attachment. In vitro and in vivo studies demonstrated that the transient β(2)-AR activation abolished normal preimplantation uterine contractility without adversely affecting blastocyst quality. The contractility inhibition is mediated by activation of the cAMP-PKA pathway and accompanied by specific down-regulation of lpa3, a gene previously found to be critical for uterine contraction and embryo spacing. These results indicated that normal uterine contraction-mediated correct intrauterine embryo distribution is crucial for successful ongoing pregnancy. Abnormal β(2)-AR activation at early pregnancy provided a molecular clue in explaining how maternal stress at early stages could adversely affect the pregnancy outcome