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.

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.