STUDY QUESTION Could erastin activate ferroptosis to regress endometriotic lesions? SUMMARY ANSWER Erastin could induce ferroptosis to regress endometriotic lesions in endometriosis. WHAT IS KNOWN ALREADY Ectopic endometrial stromal cells (EESCs) are in an iron overloading microenvironment and tend to be more sensitive to oxidative damage. The feature of erastin-induced ferroptosis is iron-dependent accumulation of lethal lipid reactive oxygen species (ROS). STUDY DESIGN, SIZE, DURATION Eleven patients without endometriosis and 21 patients with endometriosis were recruited in this study. Primary normal and ectopic endometrial stromal cells were isolated, cultured and subjected to various treatments. The in vivo study involved 10 C57BL/6 female mice to establish the model of endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS The markers of ferroptosis were assessed by cell viability, lipid peroxidation level and morphological changes. The cell viability was measured by colorimetric method, lipid peroxidation levels were measured by flow cytometry, and morphological changes were observed by transmission electron microscopy. Immunohistochemistry and western blot were used to detect ferroportin (FPN) expression. Prussian blue staining and immunofluorescent microscopy of catalytic ferrous iron were semi-quantified the levels of iron. Adenovirus-mediated overexpression and siRNA-mediated knockdown were used to investigate the role of FPN on erastin-induced ferroptosis in EESCs. MAIN RESULTS AND THE ROLE OF CHANCE EESCs were more susceptible to erastin treatment, compared to normal endometrial stromal cells (NESCs) (P<0.05). Treatment of cultured EESCs with erastin dramatically increased the total ROS level (P<0.05, versus control), lipid ROS level (P<0.05, versus NESCs) and intracellular iron level (P<0.05, versus NESCs). The cytotoxicity of erastin could be attenuated by iron chelator, deferoxamine (DFO), and ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1, (P<0.05, versus erastin) in EESCs. In EESCs with erastin treatment, shorter and condensed mitochondria were observed by electron microscopy. These findings together suggest that erastin is capable to induce EESC death by ferroptosis. However, the influence of erastin on NESCs was slight. The process of erastin-induced ferroptosis in EESCs accompanied iron accumulation and decreased FPN expression. The overexpression of FPN ablated erastin-induced ferroptosis in EESCs. In addition, knockdown of FPN accelerated erastin-induced ferroptosis in EESCs. In a mouse model of endometriosis, we found ectopic lesions were regressed after erastin administration. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION This study was mainly conducted in primary human endometrial stromal cells. Therefore, the function of FPN in vivo need to be further investigated. WIDER IMPLICATIONS OF THE FINDINGS Our findings reveal that erastin may serve as a potential therapeutic treatment for endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. The authors declare no conflict of interest.
Aberrant overexpression of long non-coding RNA CRNDE (Colorectal Neoplasia Differentially Expressed) is confirmed in various human cancers, which is correlated with advanced clinicopathological features and poor prognosis. CRNDE promotes cancer cell proliferation, migration and invasion, and suppresses apoptosis in complicated mechanisms, which result in the initialization and development of human cancers. In this review, we provide an overview of the oncogenic role and potential clinical applications of CRNDE.
Background/Aims: Excess fibrosis may lead to chronic pain, scarring, and infertility as endometriosis develops and progresses. The pathogenesis of endometriosis has been linked to transforming growth factor-β (TGF-β), the most potent promoter of fibrosis. Methods: Levels of NR4A1 and P-NR4A1 protein in human endometrial and endometriotic tissue were assessed by western blotting and immunohistochemistry. The expression levels of fibrotic markers in stromal cells were evaluated by real-time PCR. The degree of fibrosis in mouse endometriotic lesions was detected by Masson trichrome and Sirius red staining. Results: The level of phosphorylated-NR4A1 was higher in ovarian endometriotic tissue than in normal endometrium, and long-term TGF-β1 stimulation phosphorylated NR4A1 in an AKT-dependent manner and then promoted the expression of fibrotic markers. Furthermore, inhibition of NR4A1 in stromal cells increased the TGF-β1-dependent elevated expression of fibrotic markers, and loss of NR4A1 stimulated fibrogenesis in mice with endometriosis. Additionally, Cytosporone B (Csn-B), an NR4A1 agonist, effectively decreased the TGF-β1-dependent elevated expression of fibrotic markers in vitro and significantly inhibited fibrogenesis in vivo. Conclusion: NR4A1 can regulate fibrosis in endometriosis and may serve as a new target for the treatment of endometriosis.
Polycystic ovarian syndrome (PCOS) is a common endocrine disease in adolescents and women of childbearing age, also a common cause of female infertility. In recent years, studies have found that the occurrence of PCOS is related to changes in the intestinal flora. Trimethylamine N-oxide (TMAO) is an organic compound produced by intestinal microorganisms. However, the relationship between TMAO and PCOS remain mostly unexplored. The effects of TMAO on PCOS were assessed in vitro and in vivo. In a PCOS rat model, plasma TMAO, hormone and PI3K signaling levels were examined. In the process of in vitro maturation (IVM), immunofluorescence and confocal microscopy were used to detect the influence of adding different TMAO concentrations to the culture medium on oocytes. The fasting insulin (FINS), HOMA-IR, luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH) and plasma TMAO levels of the PCOS rat group were significantly higher than those of the control group. Treatment with the TMAO inhibitor 3,3-dimethyl-1-butanol (DMB) alleviated metabolic disorder in PCOS rats. In PCOS rats, DMB improved the PI3K/Akt-related signaling pathway compared to no treatment. In IVM, the mitochondria of oocytes in the TMAO groups were aggregated and distributed, and mitochondrial membrane potential and ATP content were decreased. Apoptosis was more severe in the TMAO group than in the control group. TMAO worsened metabolic dysfunction in a rat model of PCOS and decreased the mitochondrial function of oocytes in the process of IVM.
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