Iron overload in endometriosis peritoneal fluid induces early embryo ferroptosis mediated by HMOX1
Ontology highlight
ABSTRACT:
SUBMITTER: Li S
PROVIDER: S-EPMC8593044 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells. We validated the results in C57BL/6J mice and a mouse model of hemochromatosis (Hfe-/- mice). Our screen revealed that the anti-rheumatoid arthritis drug auranofin (AUR) potently upregulates hepcidin expression. Interestingly, we found that canonical signaling pathways that regulate iron, including the Bmp/Smad and IL-6/Jak2/Stat3 pathways, play indispensable roles in mediating AUR's effects. In addition, AUR induces IL-6 via the NF-?B pathway. In C57BL/6J mice, acute treatment with 5?mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation. Whereas chronically treating male Hfe-/- mice with 5?mg/kg AUR activated hepatic IL-6/hepcidin signaling, decreasing systemic iron overload, but less effective in females. Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells, providing a mechanistic explanation for ineffectiveness of AUR in female Hfe-/- mice. Notably, high-dose AUR (25?mg/kg) induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase (TXNRD) activity. We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by high-dose AUR without comprising its beneficial effect on iron metabolism. In conclusion, our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis, and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms, suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.
| S-EPMC7393508 | biostudies-literature
Project description:Endometriosis (EM) is a common chronic inflammatory disease in women. Sampson's retrograde menstruation theory is the most widely accepted theory of EM pathogenesis. The periodic bleeding of ectopic lesions is an important pathological feature of this disease, and the occurrence and progression of EM are closely associated with the iron overload caused by ectopic lesions. However, animal models that simulate menstrual-blood reflux and hemorrhage from EM lesions are lacking. In this study, we performed intraperitoneal injection of endometrial fragments and periodic intraperitoneal blood injection to simulate the real cause and disease state of EM and successfully constructed a mouse model of EM iron overload. Our research found that the number, size, and degree of adhesion of EM lesions in the iron-overload model mouse were significantly higher than those in the model mouse. Moreover, the iron concentration in the abdominal fluid and ovary significantly increased, and the level of malondialdehyde (MDA) in the ovary increased. Conversely, GPX4, GSH, and other anti-ferroptosis-related proteins were downregulated, proving the occurrence of ferroptosis. Huayu Jiedu Fang (HYJDF) is an empirical prescription for EM treatment. This study combined animal experiments, UHPLC-QE-MS analysis, and network pharmacology to analyze whether HYJDF can inhibit ferroptosis to slow down the progression of EM and protect ovarian function. Based on the constructed iron-overload model, HYJDF can reduce the volume of EM lesions and the degree of adhesion, downregulate the total iron concentration in the peritoneal fluid and ovary, upregulate GPX4 expression and GSSG in the ovary, downregulate the level of MDA in the ovary, and promote the development of follicles. We further confirmed that HYJDF can inhibit the progression of EM disease and improve the ovarian function of the model mouse by inhibiting ferroptosis. Finally, through UHPLC-QE-MS and network pharmacology analysis, the natural compounds in HYJDF were identified and verified and the regulatory effect of HYJDF on the EM ferroptosis pathway through the IL-6/hepcidin pathway was preliminarily elucidated.
| S-EPMC9448539 | biostudies-literature
Project description:Motor neuron death is supposed to result in primary motor cortex atrophy after spinal cord injury (SCI), which is relevant to poorer motor recovery for patients with SCI. However, the exact mechanisms of motor neuron death remain elusive. Here, we demonstrated that iron deposition in the motor cortex was significantly increased in both SCI patients and rats, which triggered the accumulation of lipid reactive oxygen species (ROS) and resulted in motor neuronal ferroptosis ultimately. While iron chelator, ROS inhibitor and ferroptosis inhibitor reduced iron overload-induced motor neuron death and promoted motor functional recovery. Further, we found that activated microglia in the motor cortex following SCI secreted abundant nitric oxide (NO), which regulated cellular iron homeostasis-related proteins to induce iron overload in motor neurons. Thus, we conclude that microglial activation induced iron overload in the motor cortex after SCI triggered motor neuronal ferroptosis and impeded motor functional recovery. These findings might provide novel therapeutic strategies for SCI.
| S-EPMC8105676 | biostudies-literature
Project description:Disruption of iron homeostasis is associated with multiple diseases. It has been found that patients with genetic iron overload develop massive iron deposition in the pancreas. However, few studies have focused on the effect of secondary iron overload on the pancreas. The objective of the present study was to investigate the pathogenic consequences of secondary iron overload in mice. An iron overload mouse model was constructed by intraperitoneal injection of 120 mg/kg body weight of iron dextran every other week for 12 weeks. Iron deposition, immunocyte infiltration, fibrosis, oxidative stress and ferroptosis were assessed using Prussian blue staining, immunohistochemical analysis, Masson staining, Sirius red staining, RT‑qPCR analysis and western blot analysis. It was found that iron‑overloaded mice showed pancreatic iron overload, together with elevated gene expression of the iron storage factor ferritin H, and decreased expression of the iron transportation mediator divalent metal transporter 1, ferroportin 1 and transferrin receptor. Iron‑overloaded mice developed mild pancreatitis with increased serum amylase and lipase activities, as well as elevated gene expression levels of pro‑inflammatory cytokines, including interleukin (IL)‑1β, IL‑6 and inducible nitric oxide synthase. Acinar atrophy, massive immunocyte infiltration and pancreatic fibrosis were noted in the iron‑overloaded mice. As an underlying mechanism, iron‑overloaded mice showed increased pancreatic oxidative stress, with an elevated malondialdehyde level, and decreased SOD and glutathione peroxidase activity. Furthermore, iron overload led to ferroptosis with promoted expression of cytochrome c oxidase subunit II, and decreased transcripts of glutathione peroxidase 4 and solute carrier family 7 member 11. These results provided evidence that multiple intraperitoneal injections of iron dextran in mice lead to iron overload‑induced chronic pancreatitis, which suggested that secondary iron overload is a risk factor for pancreatitis and highlights the importance of iron in maintaining the normal functions of the pancreas.
| S-EPMC9747200 | biostudies-literature
Project description:BackgroundRecent studies have shown that the accumulation of free iron and lipid peroxides will trigger a new form of cell death-ferroptosis. This form of cell death is associated with a variety of diseases, including type 2 diabetes. We hypothesize that iron overload may play a role in driving glucose metabolism abnormalities by inducing endoplasmic reticulum stress that mediates ferroptosis in islet β cells. In this study, we tested this conjecture from in vivo and in vitro experiments.MethodsWe established a mouse iron overload model by intraperitoneal injection of iron dextrose (50 mg/kg) and an iron overload cell model by treating MIN6 cells with ferric ammonium citrate (640 μmol/L, 48 h) in vitro. The iron deposition in pancreatic tissue was observed by Prussian blue staining, and the pathological changes in pancreatic tissues by HE staining and the protein expression level by pancreatic immunohistochemistry. In the cellular experiments, we detected the cell viability by CCK8 and observed the cellular ultrastructure by transmission electron microscopy. We also used MDA and ROS kits to detect the level of oxidative stress and lipid peroxidation in cells. Western blotting was performed to detect the expression levels of target proteins.ResultsIron overload induces MIN6 cell dysfunction, leading to increased fasting blood glucose, impaired glucose tolerance, and significantly decreased insulin sensitivity in mice. This process may be related to the ferroptosis of islet β cells and the activation of ASK1/P-P38/CHOP signaling pathway.
| S-EPMC10120586 | biostudies-literature
Project description:Purpose: To screen out specific protein with different concentration in follicular fluid from advanced endometriosis and determine its direct effect on mouse oocytes matured in vitro. Methods: FF samples were obtained from 25 patients (EMS group, n = 15; control group, n = 10) to screen the differential proteins by using iTRAQ Labeling and 2D LC-MS. Transferrin (TRF) in was found significantly decreased in EMS group, which was verified using ELISA in enlarged FF samples (EMS group, n = 31; control group, n = 27). The contents of ferric ion in FFs were detected by ELISA and TRF saturations were calculated in two groups. Germinal vesicle (GV) oocytes of mouse were maturated in vitro interfered with the FFs in five groups, whose concentrations of TRF were modulated, and maturation in vitro rates were compared among groups. Results: The reduced concentration of TRF with three analogs and increased concentration of ferric ion were found in the FF of the EMS group (p < 0.05). The numerical values of TSAT was 54.8% in EMS group, indicating iron overload in the FF. The EMS-FF showed significantly decreased maturation in vitro rate (p < 0.05) of mouse oocytes, which was improved with the supplementation of TRF, compared with the control-FF. The effect was blocked by the TRF antibody (p < 0.05). Conclusions: Being aware of the relatively small sample size, our results possibly suggest that TRF insufficiency and iron overload in FF from advanced EMS contribute to oocytes dysmaturity, which may be a cause of EMS-related infertility.
| S-EPMC7317002 | biostudies-literature
Project description:Endometriosis is a common inflammatory gynecological disorder which causes pelvic scarring, pain, and infertility, characterized by the implantation of endometrial-like lesions outside the uterus. The peritoneum, ovaries, and deep soft tissues are the commonly involved sites, and endometriotic lesions can be classified into three subphenotypes: superficial peritoneal endometriosis (PE), ovarian endometrioma (OE), and deep infiltrating endometriosis (DIE). In 132 women diagnosed laparoscopically with and without endometriosis (n = 73, 59 respectively), and stratified into PE, OE, and DIE, peritoneal fluids (PF) were characterized for 48 cytokines by using multiplex immunoassays. Partial-least-squares-regression analysis revealed distinct subphenotype cytokine signatures-a six-cytokine signature distinguishing PE from OE, a seven-cytokine signature distinguishing OE from DIE, and a six-cytokine-signature distinguishing PE from DIE-each associated with different patterns of biological processes, signaling events, and immunology. These signatures describe endometriosis better than disease stages (p < 0.0001). Pathway analysis revealed the association of ERK1 and 2, AKT, MAPK, and STAT4 linked to angiogenesis, cell proliferation, migration, and inflammation in the subphenotypes. These data shed new insights on the pathophysiology of endometriosis subphenotypes, with the potential to exploit the cytokine signatures to stratify endometriosis patients for targeted therapies and biomarker discovery.
| S-EPMC7278942 | biostudies-literature
Project description:ObjectiveTo demonstrate the feasibility of studying exosomes directly from peritoneal fluid, we isolated exosomes from endometriosis patient samples and from controls, and characterized their cargo.DesignCase-control experimental study.SettingAcademic clinical center.Patient (s)Women with and without endometriosis who underwent laparoscopic surgery (n = 28 in total).Intervention (s)None.Main outcome measure (s)Concentration of exosomes within peritoneal fluid and protein content of the isolated exosomes.Result (s)Peritoneal fluid samples were pooled according to the cycle phase and disease stage to form six experimental groups, from which the exosomes were isolated. Exosomes were successfully isolated from peritoneal fluid in all the study groups. The concentration varied with cycle phase and disease stage. Proteomic analysis showed specific proteins in the exosomes derived from endometriosis patients that were absent in the controls. Five proteins were found exclusively in the endometriosis groups: PRDX1, H2A type 2-C, ANXA2, ITIH4, and the tubulin α-chain.Conclusion (s)Exosomes are present in peritoneal fluid. The characterization of endometriosis-specific exosomes opens up new avenues for the diagnosis and investigation of endometriosis.
| S-EPMC7057257 | biostudies-literature
Project description:Endometriosis (EMs) occurs in approximately 50% of women with infertility. The main causes of EMs-related infertility are follicle dysplasia and reduced oocyte quality. Iron overload occurs in ovarian follicular fluid (FF) of patients with EMs, and this condition is associated with oocyte maturation disorder. However, the underlying molecular mechanism remains largely unknown. In the present study, we identified the mechanism underlying ferroptosis in ovarian granulosa cells and oocyte maturation failure in EMs based on a retrospective review of in vitro fertilization/intracytoplasmic sperm injection-frozen embryo transfer outcomes in infertile patients with EMs. Mouse granulosa cells were treated with EMs-related infertile patients' follicular fluid (EMFF) in vitro. Western blot analysis, quantitative polymerase chain reaction, fluorescence staining, and transmission electron microscopy were used to assess granulosa cells ferroptosis. The effects of exosomes were examined by nanoparticle tracking analysis, RNA-seq, and Western blot analysis. Finally, the therapeutic values of vitamin E and iron chelator (deferoxamine mesylate) in vivo were evaluated in an EMs-related infertility model. Patients with ovarian EMs experienced poorer oocyte fertility than patients with non-ovarian EMs. We observed that EMFF with iron overload-induced granulosa cell ferroptosis in vitro and in vivo. Mechanically, nuclear receptor coactivator four-dependent ferritinophagy was involved in this process. Notably, granulosa cells undergoing ferroptosis further suppressed oocyte maturation by releasing exosomes from granulosa cells. In therapeutic studies, vitamin E and iron chelators effectively alleviated EMs-related infertility models. Our study indicates a novel mechanism through which EMFF with iron overload induces ferroptosis of granulosa cells and oocyte dysmaturity in EMs-related infertility, providing a potential therapeutic strategy for EMs-related infertility.
| S-EPMC9253011 | biostudies-literature
Project description:BackgroundSanguinarine chloride (S.C) is a benzophenanthrine alkaloid derived from the root of sanguinaria canadensis and other poppy-fumaria species. Studies have reported that S.C exhibits antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory effects, which contribute to its anti-cancer properties. Recent studies suggested that the antitumor effect of S.C through inducing ferroptosis in some cancers. Nevertheless, the precise mechanism underlying the regulation of ferroptosis by S.C remains poorly understood.MethodsA small molecule library was constructed based on FDA and CFDA approved small molecular drugs. CCK-8 assay was applied to evaluate the effects of the small molecule compound on tumor cell viability. Prostate cancer cells were treated with S.C and then the cell viability and migration ability were assessed using CCK8, colony formation and wound healing assay. Reactive oxygen species (ROS) and iron accumulation were quantified through flow cytometry analysis. The levels of malondialdehyde (MDA) and total glutathione (GSH) were measured using commercially available kits. RNA-seq analysis was performed to identify differentially expressed genes (DEGs) among the treatment groups. Western blotting and qPCR were utilized to investigate the expression of relevant proteins and genes. In vivo experiments employed a xenograft mice model to evaluate the anti-cancer efficacy of S.C.ResultsOur study demonstrated that S.C effectively inhibited the viability of various prostate cancer cells. Notably, S.C exhibited the ability to enhance the cytotoxicity of docetaxel in DU145 cells. We found that S.C-induced cell death partially relied on the induction of ferroptosis, which was mediated through up-regulation of HMOX1 protein. Additionally, our investigation revealed that S.C treatment decreased the stability of BACH1 protein, which contributed to HMOX1expression. We further identified that S.C-induced ROS caused BACH1 instability by suppressing USP47expression. Moreover, In DU145 xenograft model, we found S.C significantly inhibited prostate cancer growth, highlighting its potential as a therapeutic strategy. Collectively, these findings provide evidence that S.C could induce regulated cell death (RCD) in prostate cancer cells and effectively inhibit tumor growth via triggering ferroptosis. This study provides evidence that S.C effectively suppresses tumor progression and induces ferroptosis in prostate cancer cells by targeting ROS/USP47/BACH1/HMOX1 axis.ConclusionThis study provides evidence that S.C effectively suppresses tumor progression and induces ferroptosis in prostate cancer cells by targeting the ROS/USP47/BACH1/HMOX1 axis. These findings offer novel insights into the underlying mechanism by which S.C inhibits the progression of prostate cancer. Furthermore, leveraging the potential of S.C in targeting ferroptosis may present a new therapeutic opportunity for prostate cancer. This study found that S.C induces ferroptosis by targeting the ROS/USP47/BACH1/HMOX1 axis in prostate cancer cells.
| S-EPMC10777654 | biostudies-literature