The protective effects of Ferrostatin-1 against inflammation-induced preterm birth and fetal brain injury.

INTRODUCTION: Recent studies have suggested the involvement of ferroptosis in preterm birth. Despite compelling evidence, the underlying mechanism remains unknown. This investigation aimed to determine the therapeutic effects of Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, in preterm birth and fetal brain injury. METHODS: Human placenta samples and clinical data of participants were collected to ascertain whether placental ferroptosis was associated with preterm birth. Lipopolysaccharide (LPS)-induced preterm birth mouse model was used to examine the protective effects of Fer-1 on preterm birth. Fetal brain tissues and offspring mice at 5 and 8 weeks were studied to determine the effects of Fer-1 on the cognitive function of offspring. RESULTS: We examined the mechanism of spontaneous preterm birth and discovered that placental ferroptosis was associated with preterm birth. Fer-1 inhibited preterm birth by ameliorating placental ferroptosis and maternal inflammation, thus improving LPS-induced intrauterine inflammation to maintain pregnancy. Antenatal administration of Fer-1 prevented LPS-induced fetal brain damage in the acute phase and improved long-term neurodevelopmental impairments by improving placental neuroendocrine signaling and maintaining placental function. CONCLUSION: Fer-1 inhibited preterm birth and fetal brain injury by inhibiting maternal inflammation and improving placental function. Our findings provide a novel therapeutic strategy for preterm birth.

Targeting Mitochondrial Oxidative Stress to Protect Against Preterm Birth and Fetal Brain Injury via Nrf2 Induction.

Aims: Preterm birth (PTB), recognized as delivery before 37 weeks of gestation, is a multifactorial syndrome characterizing as the main cause of neonatal mortality. Reactive oxygen species (ROS) have been identified as proinflammatory factors to cause placental inflammation, thereby resulting in several pregnancy outcomes. To date, limited knowledge regarding the underlying mechanisms of ROS-induced PTB has been reported. In this study, we aimed to investigate the role of oxidative stress in PTB and the protective effects of mitochondria-targeted antioxidant MitoTEMPO (MT) on preterm labor and offspring mice. Results: In this study, we found that preterm placentas had abnormal mitochondrial function, oxidative stress, and inflammatory response. In the lipopolysaccharide (LPS)-induced PTB mouse model, MT inhibited PTB by ameliorating maternal oxidative stress and inflammation, especially in placentas, thus improving placental function to maintain pregnancy. Antenatal administration of MT prevented LPS-induced fetal brain damage in acute phase and improved long-term neurodevelopmental impairments. Furthermore, our in vitro investigations validated that MT retarded the ROS accumulation and inflammatory response in LPS-stimulated trophoblast cells by promoting Kelch-like ECH-associated protein 1 (Keap1) degradation and subsequently activating nuclear factor erythroid 2-related factor 2 (Nrf2). By inhibiting Nrf2 activation, we discovered that the anti-inflammation and protective characteristics of MT were Nrf2/ARE pathway dependent. Innovation and Conclusion: MT inhibited PTB and fetal brain injury by inhibiting maternal inflammation and improving placental function through Keap1/Nrf2/antioxidant response element signaling pathway. Our findings provide a novel therapeutic strategy for PTB.

The Role of Formyl Peptide Receptor 1 in Uterine Contraction During Parturition.

Parturition involves the transformation of the quiescent myometrium into a highly excitable and contractile state, a process that is driven by changes in myometrial gene expression. This study aimed to identify myometrial transcriptomic signatures and potential novel hub genes in parturition, which have great significance for understanding the underlying mechanisms of successful parturition and treating labor-associated pathologies such as preterm birth. In our study, comparative transcriptome analysis was carried out on human myometrial tissues collected from women undergoing caesarean section at term in the presence (TL = 8) and absence of labor (TNL = 8). A total of 582 differentially expressed genes (DEGs) between TL and TNL tissues were identified. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) and gene set enrichment analysis (GSEA) revealed that the DEGs were enriched in signal transduction, regulation of signaling receptor activity, inflammatory response, cytokine-cytokine receptor interaction, IL-17 signaling pathway, TNF signaling pathway, among others. Thus, transcriptome analysis of the myometrium during term labor revealed that labor onset was associated with an inflammatory response. Moreover, protein-protein interactions network analysis identified FPR1, CXCL8, CXCL1, BDKRB2, BDKRB1, and CXCL2 as the hub genes associated with onset of labor. Formyl peptide receptor 1 (FPR1) was highly expressed in laboring myometrial tissues, with the activation of FPR1 in vitro experiments resulting in increased myometrial contraction. Our findings demonstrate the novel role of FPR1 as a modulator of myometrial contraction.

Ezrin T567 phosphorylation regulates migration and invasion of ectopic endometrial stromal cells by changing actin cytoskeleton.

AIMS: The enhanced ability of endometrial cell migration and invasion is the foundation for formation of ectopic lesions in endometriosis. Ezrin has been reported to regulate cell motility by remodeling the cytoskeleton. However, little is known about the mechanisms through which ezrin remodels the cytoskeleton and cell structure to promote cell motility in endometriosis. METHODS: In our study, expression and distribution of ezrin, and Rho pathway were detected through immunohistochemical analysis. The effects of inhibiting ezrin T567 phosphorylation on Rho signaling pathway and cytoskeleton were investigated through western blot, transmission electron microscopy and immunofluorescence analysis. KEY FINDINGS: We found that the expression of ezrin and Rho pathway was higher in ectopic endometrium. NSC305787 inhibited the phosphorylation of ezrin T567, resulting in decreased expression of Rho pathway and reduced filopodia formation in ectopic endometrial stromal cells. SIGNIFICANCE: Taken together, our study suggested that ezrin T567 phosphorylation modulated migration and invasion of ectopic ESCs through actin reconstructions, which may serve as a novel therapeutic target in ovarian endometriosis.

Fertility performance and the predictive value of the endometriosis fertility index staging system in women with recurrent endometriosis: A retrospective study.

This study presents the postoperative pregnancy rate of women with recurrent endometriosis and evaluates the predictive value of the endometriosis fertility index (EFI) for the pregnancy.A total of 107 women who wished to conceive after surgery for recurrent endometriosis from January 2007 to December 2016 were included. The EFI score was calculated postoperatively. The receiver operator characteristic (ROC) curve was plotted to determine the most promising contributor to predicting pregnancy, and Kaplan-Meier (K-M) analysis was used to estimate the cumulative pregnancy rate (CPR).A total of 61 pregnancies were registered in 58 women and the remaining 49 patients failed to become pregnant. The EFI score was strongly associated with the postoperative fertility prognosis. The CPRs during the first 2 and 3 years postoperatively were 51.86% and 66.38%, respectively, and increased to 71.98% within the first 5 years postoperatively in patients with EFI scores ≥5. However, the CPR was 26.00% during the first 2 years after surgery in individuals with EFI scores <5, and there was no increase in the CRP thereafter.Women suffering from recurrent endometriosis still experienced a probability of natural pregnancy, especially patients with EFI scores ≥5. The EFI score had good predictive power for postoperative pregnancy in these patients.

Mitochondria and oxidative stress in ovarian endometriosis.

Endometriosis is associated with inflammatory reaction, and reactive oxidative species (ROS) are highly pro-inflammatory factors. Mitochondria are responsible for the production of ROS and energy. However, little is known about how mitochondria regulate ROS generation and energy metabolism in endometriosis. In our study, we investigated mitochondrial structure and function of ectopic endometrial stromal cells (ESCs) in ovarian endometriosis. We found mitochondria in ectopic ESCs generated more ROS and energy than controlled groups. Mitochondrial superoxide dismutase (SOD2), as an antioxidant enzyme, was found highly expressed in ectopic endometrium compared with normal endometrium. Due to its antioxidant role, SOD2 promoted the development of endometriosis by maintaining functional mitochondria to support high energetic metabolism of ectopic ESCs. We also showed that SOD2 promoted cell proliferation and migration in ovarian endometriosis. Inhibiting SOD2 expression reduced proliferation and migration of ectopic ESCS, and increased cell apoptosis. Therefore, understanding the role of mitochondrial dysfunction and SOD2 in ovarian endometriosis may provide new strategies to treat this disease.

Prophylactic uterine artery embolization in second-trimester pregnancy termination with complete placenta previa.

OBJECTIVE: This study was performed to assess whether prophylactic uterine artery embolization (UAE) is beneficial for second-trimester abortion with complete placenta previa (CPP). METHODS: Patients with CPP who underwent second-trimester pregnancy termination by labor induction with or without UAE from January 2010 to January 2018 were retrospectively reviewed. In total, 25 patients were eligible for analysis. The primary outcomes were the abortion success rate and bleeding volume, and the secondary outcomes were the induction-to-abortion time, length of hospital stay, and complications. RESULTS: CPP occurred in all 25 patients. Fifteen patients underwent prophylactic UAE (UAE group) and 10 did not (control group). Abortion was successful in 13 of 15 (86.7%) women in the UAE group and in 9 of 10 (90.0%) women in the control group. There was no significant difference in the bleeding volume or induction-to-abortion time between the two groups. The hospital stay was longer and pyrexia was more common in the UAE than control group. CONCLUSION: Prophylactic UAE did not markedly improve the outcomes of second-trimester abortion in patients with CPP. Conversely, it may increase the risk of complications and prolong the hospital stay.

Polychlorinated biphenyl 104 promotes migration of endometrial stromal cells in endometriosis.

Polychlorinated biphenyls (PCBs), as part of environmental contaminants, have been proved to be related to endometriosis. This study is to investigate the effect of PCB 104 on cell migration, invasion and resultant gene expression in endometrial stromal cells (ESCs). Fifty-three specimens of eutopic endometrial tissues were collected from twenty-four women with endometriosis (EU-EMS) and twenty-nine women without endometriosis (EU-NON). Both EU-EMS and EU-NON were divided into the PCB 104 exposure group and the control group according to whether they were exposed to PCB 104. Primary cultured ESCs were exposed to PCB 104 at the micro molar doses (2 × 10-3, 0.2 and 1 µmol/L) and concentrations of 2, 5 and 10 µmol/L in six-well plates. Cell mobility and proliferation assay were used to evaluate the effects of PCB 104 on the migration, invasion and proliferation of ESCs, and the effect of PCB 104 on actin cytoskeleton was also examined by immunofluorescence. Subsequently, the mRNA levels of related genes including matrix metalloproteinase (MMP) -2, -3, -9, -10, E-cadherin, Snail, Slug and tissue inhibitor of metalloproteinase (TIMP) -2 in ESCs were examined by using real-time PCR, as well as protein levels of MMP-3 and MMP-10 were detected by enzyme-linked immunosorbent assay (ELISA). We explored the role of epidermal growth factor receptor (EGFR) in the expression of MMP-3 and MMP-10 induced by PCB 104. Exposure to PCB 104 significantly increased the migration and invasion of ESCs. The mRNA and protein levels of MMP-3 and MMP-10 in ESCs treated with PCB 104 were higher than that in the control, with a dose- and time-dependent manner in mRNA level, while the expression of MMP-2, MMP-9, TIMP-2, E-cadherin, Snail and Slug did not change significantly. Taken together, PCB 104 promotes migration and invasion of ESCs by inducing the expression of MMP-3 and MMP-10, which may involved the EGFR signalling pathway.