Metformin may induce immunologic tolerance at the maternal-foetal interface in early human pregnancy.

OBJECTIVE: Repeated pregnancy loss has been shown to be related to decidual immune imbalance. Metformin has been found to promote a shift in the Th17/Treg balance towards immune tolerance. Our research aims to evaluate and obtain further information on the role and potential mechanism of metformin on Th17/Treg balance in the early pregnancy decidua. METHODS: Decidual immune cells from normal pregnancy women were treated with metformin, pro-inflammatory cytokines or metformin + cytokines respectively. The mRNA expression levels of STAT3, STAT5, RORC and Foxp3 were detected by qRT-PCR. The proportions of Th17 and Treg cells, the stability of Treg cells, and the STATs phosphorylation levels of T cells were evaluated by flow cytometry. The cytokine concentrations in the culture medium were detected by ELISA. RESULTS: After treated with metformin, indicators related to immune tolerance, including the mRNA expression and phosphorylation levels of STAT5, mRNA expression level of Foxp3, the proportion of Treg cell, and the IL-10 concentration increased significantly. Indicators related to immune rejection including the mRNA expression level of STAT3, the proportion of Th17 cell, and the IL-17A concentration showed a significant decrease. In inflammatory conditions, the proportion of Th-like Treg cells increased. Metformin promoted CD25 expression to maintain Treg cell stability. CONCLUSION: Metformin has beneficial effects on immunological tolerance at the maternal-foetal interface in early pregnancy. The underlying mechanism may be that metformin restores the Th17/Treg balance by changing the expression of STATs, which is conducive to establishing maternal-foetal immune tolerance.

Ferroptosis contributes to catecholamine-induced cardiotoxicity and pathological remodeling.

High levels of circulating catecholamines cause cardiac injury, pathological remodeling, and heart failure, but the underlying mechanisms remain elusive. Here we provide both in vitro and in vivo evidence that excessive ß-adrenergic stimulation induces ferroptosis in cardiomyocytes, revealing a novel mechanism for catecholamine-induced cardiotoxicity and remodeling. We found that isoproterenol, a synthetic catecholamine, promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to GPX4 inactivation and enhanced lipid peroxidation. Isoproterenol also promoted heme oxygenase 1 (HO-1) expression by downregulating the transcription suppressor BTB and CNC homology 1 (Bach1), leading to increased labile iron accumulation through heme degradation. Moreover, isoproterenol markedly induced the accumulation of free iron and lipid reactive oxygen species (ROS) in the mitochondria, while targeted inhibition of iron overload and ROS accumulation within mitochondria effectively inhibited ferroptosis in cardiomyocytes. Importantly, isoproterenol administration markedly induced ferroptosis in the myocardium in vivo, associated with elevated non-heme iron accumulation driven by HO-1 upregulation. Strikingly, blockade of ferroptosis with ferrostatin-1 or inhibition of HO-1 activity with zinc protoporphyrin (ZnPP) effectively alleviated cardiac necrosis, pathological remodeling, and heart failure induced by isoproterenol administration. Taken together, our results reveal that catecholamine stimulation primarily induces ferroptotic cell death in cardiomyocyte through GPX4 and Bach1-HO-1 dependent signaling pathways. Targeting ferroptosis may represent a novel therapeutic strategy for catecholamine overload-induced myocardial injury and heart failure.

Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.

Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.

The expression profile of plasmatic exosomal lncRNAs in early-onset preeclampsia by sequencing.

Identification of the expression profile of exosomal lncRNAs in plasma from PE patients to provide new insights into the molecular mechanism. Five pregnant patients with early-onset severe PE were included in the PE group and 5 normal pregnant patients were included in the control group in the training cohort. Differential expression of genes were identified between the two groups, and were verified in plasma exosomes from 12 additional pregnant patients with EPE and 12 normal pregnant patients. KEGG pathway analysis and GO enrichment analysis were performed using online prediction databases to construct a lncRNA-miRNA-mRNA co-expression network. From there a panel of candidate lncRNAs was selected and validated via quantitative PCR in the two groups. In the 289 differential lncRNA, 155 were up-regulated and 134 were down-regulated. Bioinformatics enrichment analysis demonstrated that the target genes of differential expression of lncRNAs were enriched in 159 pathways with P < 0.05, including cancer, metabolic and PI3K-Akt signaling pathways. Three lncRNAs exhibited significant differential expressed in exosomes between the two groups. A lncRNA-miRNA-mRNA co-expression network analysis showed that ENST00000559730-hsa-miR-661-NUDT16 was the most frequently associated with susceptibility-relation of PE. The significant differences of plasmatic exosomal lncRNA expression between normal pregnant women and early-onset severe PE patients suggest that lncRNA may participate in the pathogenetic process of PE. Our study provides a preliminary bioinformatic foundation in order to find PE markers in plasma which further increase the sample size, and continue to verify the function of lncRNA in vitro.

TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis.

Mutations in TGF-ß-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.

Diagnosis and treatment discussion of congenital factor VII deficiency in pregnancy: A case report.

BACKGROUND: Congenital factor VII deficiency (FVIID) is a rare autosomal recessive genetic disorder. The clinical manifestations of this deficiency vary greatly. Predicting the risk of bleeding during and after childbirth of pregnant women with congenital FVIID is difficult. Recombinant factor VIIa is the most common replacement therapy for FVIID. However, no unified diagnosis and treatment plan for pregnant women with congenital FVIID has been established. CASE SUMMARY: We report the clinical history of a pregnant woman who was considered to have congenital FVIID. Recombinant factor VIIa was prophylactically administered to the pregnant woman at the time of cervical fully opening. She successfully delivered a live infant without any complications, such as postpartum hemorrhage, neonatal abnormalities, and so on. CONCLUSION: Prophylaxis of recombinant factor VIIa during delivery can effectively reduce the incidence of postpartum hemorrhage among pregnant women with congenital FVIID associated with a high risk of bleeding.

The relationship between ovarian endometriosis and clinical pregnancy and abortion rate based on logistic regression model.

In order to study the relationship between ovarian endometriosis and clinical pregnancy, explore the correlation between endometriosis (EMT) and abortion rate and its mechanism, and provide a new theoretical basis for clinical diagnosis as well as treatment of endometriosis, in this study, pelvic endometriosis under 40 years old and have in vitro fertilization-embryo transfer (IVF-ET) operation will be selected as subjects of study. SPSS20.0 statistical software is used to analyze the data. When the measurement data between groups are compared, it is necessary to use t-test. It is necessary to use mean ± standard deviation ( x ¯ ± s ) to expressed the results. When the counting data between groups is compared, it is necessary to use Chi-square test. Finally, the binomial classification logistic regression model is established by stepwise regression method to screen out the significant factors. The results show that the infertility duration of ovarian endometriosis cyst is (3.1 ± 1.9). The infertility years of other pelvic endometriosis are (3.9 ± 2.2). The infertility years of ovarian endometriosis cyst group are shorter than those of other pelvic endometriosis groups. Significant difference cannot be seen in follicle stimulating hormone (FSH) between the two groups of patients, and the basal FSH of other pelvic endometriosis groups is obviously lower in the two groups between the ages of 29 and 40 years. In the ovarian endometriotic cyst group, the significant difference can be seen (P < 0.05). Moreover, in the comparison of ovulation induction, the Gn dosage of fresh-cycle ovarian endometriosis patients is obviously higher than that of patients with ovarian endometriosis during the freezing cycle. The fertilization rate of patients with fresh cycle ovarian endometriosis is higher than that of patients with ovarian endometriosis during the freezing cycle. The two groups of patients with the factor of ovarian endometriosis after fresh embryo transplantation and the factor of fallopian tube are compared, and the abortion rate of the ovarian endometriosis group is lower than that of the fallopian tube group. Therefore, controlling the development of ovarian endometriosis can help to improve the pregnancy rate, reduce the abortion rate and improve the pregnancy outcome of patients with ovarian endometriosis.

NFκB promotes oxidative stress-induced necrosis and ischemia/reperfusion injury by inhibiting Nrf2-ARE pathway.

In this study, we identified an unexpected pro-cell death role for NFκB in mediating oxidative stress-induced necrosis, and provide new mechanistic evidence that NFκB, in cooperation with HDAC3, negatively regulates Nrf2-ARE anti-oxidative signaling through transcriptional silencing. We showed that genetic inactivation of NFκB-p65 inhibited, whereas activation of NFκB promoted, oxidative stress-induced cell death and HMGB1 release, a biomarker of necrosis. Moreover, NFκB-luciferase activity was elevated in cardiomyocytes after simulated ischemia/reperfusion (sI/R) or doxorubicin (DOX) treatment, and inhibition of NFκB with Ad-p65-shRNA or Ad-IκBαM diminished sI/R- and DOX-induced cell death and HMGB1 release. Importantly, NFκB negatively regulated Nrf2-ARE activity and the expression of antioxidant proteins. Mechanistically, co-immunoprecipitation revealed that p65 was required for Nrf2-HDAC3 interaction and transcriptional silencing of Nrf2-ARE activity. Further, the ability of HDAC3 to repress Nrf2-ARE activity was lost in p65 deficient cells. Pharmacologic inhibition of HADCs or NFκB with trichostatin A (TSA) or BMS-345541, respectively, increased Nrf2-ARE activity and promoted cell survival after sI/R. In vivo, NFκB transcriptional activity in the mouse heart was significantly elevated after ischemia/reperfusion (I/R) injury, which was abolished by cardiomyocyte-specific deletion of p65 using p65fl/flNkx2.5-Cre mice. Moreover, genetic ablation of p65 in the mouse heart attenuated myocardial infarct size after acute I/R injury and improved cardiac remodeling and functional recovery after chronic myocardial infarction. Thus, our results identified NFκB as a key regulator of oxidative stress-induced necrosis by suppressing the Nrf2-ARE antioxidant pathway through an HDAC3-dependent mechanism. This study also revealed a new pathogenic role of NFκB in cardiac ischemic injury and pathological remodeling.

Homocysteine, endothelin-1 and nitric oxide in patients with hypertensive disorders complicating pregnancy.

OBJECTIVE: To investigate the change of level of serum homocysteine (Hcy), endothelin-1 (ET-1) and nitric oxide (NO) and clinical significance in patients with HDCP. METHODS: Two hundred and thirty nine patients with HDCP (137 patients with mild preeclampsia, 102 patients with severe preeclampsia) who were hospitalized between June 2012 and June 2015 and 200 normal pregnancy women in outpatient department were enrolled in our study were divided into HDCP group and control group. Serum Hcy concentration was measured by enzymatic cycling assay. ET-1 concentration was measured by enzyme linked immunosorbent assay. And no concentration was measured by nitrate reductase assay. RESULTS: Serum Hcy and ET-1 in HDCP group were significantly higher as compared to control group (P<0.05). Level of serum NO in HDCP group was significantly lower than in the control group (P<0.05). Level of serum Hcy and ET-1 in mild and severe preeclampsia group were significantly higher as compared to control group, respectively (P<0.05). Level of serum NO in mild and severe preeclampsia group were significantly lower than in the control group' respectively (P<0.05). Level of serum Hcy and ET-1 in severe preeclampsia group were significantly higher as compared to mild preclampsia group (P<0.05). Level of serum NO in severe preeclampsia group were significantly lower than in mild preeclampsia group (P<0.05). Spearman rank correlation analysis showed that level of serum Hcy and ET-1 was positively correlated with severity of diseases (r=0.689, 0.718, P<0.05). Level of serum NO was negatively correlated with severity of diseases (r=-0.702, P<0.05). CONCLUSION: Serum Hcy, ET-1 and NO were associated with pathogenesis of HDCP. Comprehensively measurement of them could effectively evaluate the incidence and progress of HDCP.

The use of glyburide in the management of gestational diabetes mellitus: a meta-analysis.

PURPOSE: Glyburide has been used for managing gestational diabetes mellitus (GDM) in a number of countries. It is rather inexpensive. However, its efficacy and safety remain controversial. With this meta-analysis, we evaluated glyburide in comparison with insulin. MATERIAL/METHODS: With a systematic literature search strategy, a total of 93 randomized controlled trials (RCTs) with insulin and glyburide comparison were identified. Based on the revised Consolidated Standards of Reporting Trials (CONSORT) checklist, five of them met the inclusion criteria and were included in this meta-analysis. RESULTS: Six hundred and seventy four subjects were included in these five RCTs. When compared with insulin, glyburide had an increased relative risk (RR) for neonatal hypoglycemia (RR: 1.98; 95% confidence interval [CI]: 1.17, 3.36). Estimation of standard mean differences (SMD) showed that both fetal birth weight and incidence of macrosomia were higher in subjects receiving glyburide than in those receiving insulin (SMD: 0.21; 95% CI: 0.06, 0.36; RR: 2.22; 95% CI: 1.07, 4.61 respectively). There were no significant differences in maternal glucose control, glycated hemoglobin, the rate of Cesarean section, large-for-gestational age, neonatal hypocalcemia, length of stay for neonatal ICU admissions, preterm birth, or congenital anomalies. CONCLUSIONS: Our study suggested that in women with GDM, glyburide is as effective as insulin, but the risks of neonatal hypoglycemia, high fetal birth weight, and macrosomia were higher.