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Schematic diagram of the EMP system and exposure scenarios. (A) shows the schematic diagram of the EMP system. (B,C) show the EMP exposure scenarios of rat and cells, respectively.
Source publication
Electromagnetic pulse (EMP) radiation was reported to be harmful to hippocampal neurons. However, the mechanism underlying EMP-induced neuronal damage remains unclear. In this paper, for the first time, we attempted to investigate the involvement of ferroptosis in EMP-induced neuronal damage and its underlying mechanism. In vivo studies were conduc...
Citations
... In addition, observation of changes in mitochondrial morphology by TEM is also regarded as an accessible and accurate way to evaluate ferroptosis (Yang et al. 2021). Studies have indicated that decreases in the antioxidant function of GSH and GPX4 are critical contributors to ferroptosis (Bersuker et al. 2019;Lai et al. 2022;Yang and Stockwell 2016). Given that enhancing GPX4 expression can prevent ferroptosis and ameliorate hippocampal neuron loss and cognitive impairment, targeting ferroptosis may be a valid therapeutic strategy for neurodegenerative diseases. ...
Background
Neuronal ferroptosis plays a critical role in the pathogenesis of cognitive deficits. The present study explored whether artemisinin protected type 2 diabetes mellitus (T2DM) mice from cognitive impairments by attenuating neuronal ferroptosis in the hippocampal CA1 region.
Methods
STZ-induced T2DM mice were treated with artemisinin (40 mg/kg, i.p.), or cotreated with artemisinin and Nrf2 inhibitor MEL385 or ferroptosis inducer erastin for 4 weeks. Cognitive performance was determined by the Morris water maze and Y maze tests. Hippocampal ROS, MDA, GSH, and Fe ²⁺ contents were detected by assay kits. Nrf2, p-Nrf2, HO-1, and GPX4 proteins in hippocampal CA1 were assessed by Western blotting. Hippocampal neuron injury and mitochondrial morphology were observed using H&E staining and a transmission electron microscope, respectively.
Results
Artemisinin reversed diabetic cognitive impairments, decreased the concentrations of ROS, MDA and Fe ²⁺ , and increased the levels of p-Nr2, HO-1, GPX4 and GSH. Moreover, artemisinin alleviated neuronal loss and ferroptosis in the hippocampal CA1 region. However, these neuroprotective effects of artemisinin were abolished by Nrf2 inhibitor ML385 and ferroptosis inducer erastin.
Conclusion
Artemisinin effectively ameliorates neuropathological changes and learning and memory decline in T2DM mice; the underlying mechanism involves the activation of Nrf2 to inhibit neuronal ferroptosis in the hippocampus.
Graphical Abstract
... Ferroptosis was shown to directly induce neuronal cell death in immediately derived rat organotypic hippocampal slices cultured with glutamate (Lai et al., 2022). Iron chelators and ferrostatin can block glutamate-induced ferroptosis . ...
Cardiovascular diseases (CVDs) are a leading factor driving mortality worldwide. Iron, an essential trace mineral, is important in numerous biological processes, and its role in CVDs has raised broad discussion for decades. Iron-mediated cell death, namely ferroptosis, has attracted much attention due to its critical role in cardiomyocyte damage and CVDs. Furthermore, ferritinophagy is the upstream mechanism that induces ferroptosis, and is closely related to CVDs. This review aims to delineate the processes and mechanisms of ferroptosis and ferritinophagy, and the regulatory pathways and molecular targets involved in ferritinophagy, and to determine their roles in CVDs. Furthermore, we discuss the possibility of targeting ferritinophagy-induced ferroptosis modulators for treating CVDs. Collectively, this review offers some new insights into the pathology of CVDs and identifies possible therapeutic targets.
... Besides, the iron-dependent Fenton chain reaction may be key to ferroptosis, which is associated with phospholipid hydroperoxides (PLOOHs)-a form of lipid-based ROS [100]. PLOOHs are normally reduced to their alcohols by glutathione peroxidase 4 (GPX4) in the presence of GSH as an essential cofactor [101]. When sepsis-induced GSH depletion occurs, which in turn leads to GPX4 inactivation, the inability to remove the lipid peroxides generated in the phospholipid membrane causes massive lipid peroxidation and eventually leads to cell death [68,69]. ...
Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction secondary to infection, and the severity can range from mild delirium to deep coma. Disorders of iron metabolism have been proven to play an important role in a variety of neurodegenerative diseases by inducing cell damage through iron accumulation in glial cells and neurons. Recent studies have found that iron accumulation is also a potential mechanism of SAE. Systemic inflammation can induce changes in the expression of transporters and receptors on cells, especially high expression of divalent metal transporter1 (DMT1) and low expression of ferroportin (Fpn) 1, which leads to iron accumulation in cells. Excessive free Fe2+ can participate in the Fenton reaction to produce reactive oxygen species (ROS) to directly damage cells or induce ferroptosis. As a result, it may be of great help to improve SAE by treatment of targeting disorders of iron metabolism. Therefore, it is important to review the current research progress on the mechanism of SAE based on iron metabolism disorders. In addition, we also briefly describe the current status of SAE and iron metabolism disorders and emphasize the therapeutic prospect of targeting iron accumulation as a treatment for SAE, especially iron chelator. Moreover, drug delivery and side effects can be improved with the development of nanotechnology. This work suggests that treating SAE based on disorders of iron metabolism will be a thriving field.
... Both ferroptosis and oxidative stress-induced molecular processes have two common molecular targets, namely, de ciency of Glutathione (GSH) and lipid peroxidation [10,11]. The GSH/GPX4 axis can be upregulated by electromagnetic pulses (EMP), leading to the accumulation of lipid peroxide and causing ferroptosis in hippocampus neurons [12]. Furthermore, researchers have found that ionizing radiation can induce ferroptosis in hematopoietic progenitors derived from mouse bone marrow [13]. ...
Background
In recent years, there has been increased examination of the harmful impacts of radiofrequency electromagnetic radiation (RF-EMR) on male reproductive ability, making it critical to explore effective protective measures. Melatonin has antioxidant and anti-apoptotic effects, and there is growing evidence that melatonin is beneficial to the reproductive process. The understanding of melatonin's biochemical mechanisms in safeguarding against testicular damage from RF-EMR exposure is limited.
Results
During the present investigation, it was observed that prolonged (8 weeks) exposure to RF-EMR [2.0 GHz; power density, 2.5 W/m²; systemic specific absorption rate (SAR), 0.125-0.5 W/kg] may lead to decreased testosterone and melatonin concentrations in the serum, reduced sperm quality, increased apoptosis levels, and elevated oxidative stress in male mice. Notably, the administration of melatonin (at a dosage of 10 mg/kg via intraperitoneal injection) mitigated the oxidative harm to the testicles and ferroptosis caused by RF-EMR in mice. Mechanistically, melatonin may inhibit ROS production and ferroptosis by stimulating the Nrf2 signaling pathway through its receptors (MT1/MT2).
Conclusion
Taken together, these results indicate that melatonin could potentially improve oxidative harm caused by RF-EMR in the testes of mice by blocking ferroptosis through the activation of the Nrf2 pathway via MT1/MT2 receptors.
... EMP is a high voltage pulse with a broad bandwidth, high energy, and a short pulse duration (Tian et al. 2020). Previous studies suggested that either MW or EMP single exposure could induce learning and memory impairment (Tian et al. 2020;Li et al. 2019;Wang et al. 2017;Hao et al. 2018;Deshmukh et al. 2015;Li et al. 2022;Mumtaz et al. 2022;Wang et al. 2023a, b;Hao et al. 2022;Lai et al. 2022). However, real public and occupational environments are usually filled with various types of electromagnetic waves. ...
... Previous studies demonstrated that either MW or EMP single exposure at certain doses could cause learning and (Deshmukh et al. 2015;Zhu et al. 2021;Zhi et al. 2018;Shahin et al. 2018;Lai et al. 2022). Zhu RQ et al. (Zhu et al. 2021) found that 10 mW/cm 2 1.5 GHz MW exposure led to learning and memory impairments and hippocampal structure damage in rats. ...
... Zhu RQ et al. (Zhu et al. 2021) found that 10 mW/cm 2 1.5 GHz MW exposure led to learning and memory impairments and hippocampal structure damage in rats. Our previous works reported that in vivo exposure of rats to EMP radiation at 400 ± 25 kV/m (total 400 pulses) impaired learning and memory abilities (Lai et al. 2022). In our study, we found that either 1.5 GHz MW radiation or 400 kV/m EMP single exposure could induce learning and memory decline, which was consistent with these previous studies. ...
Microwave (MW) and electromagnetic pulse (EMP) are considered environmental pollutants, both of which can induce learning and memory impairments. However, the bioeffects of combined exposure to MW and EMP have never been explored. This paper aimed to investigate the effects of combined exposure to MW and EMP on the learning and memory of rats as well as its association with ferroptosis in the hippocampus. In this study, rats were exposed to EMP, MW, or EMP and MW combined radiation. After exposure, impairment of learning and memory, alterations in brain electrophysiological activity, and damage to hippocampal neurons were observed in rats. Moreover, we also found alterations in ferroptosis hallmarks, including increased levels of iron, lipid peroxidation, and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA, as well as downregulation of glutathione peroxidase 4 (GPX4) protein in the rat hippocampus after exposure. Our results suggested that either single or combined exposure to MW and EMP radiation could impair learning and memory and damage hippocampal neurons in rats. Moreover, the adverse effects caused by the combined exposure were more severe than the single exposures, which might be due to cumulative effects rather than synergistic effects. Furthermore, ferroptosis in the hippocampus might be a common underlying mechanism of learning and memory impairment induced by both single and combined MW and EMP exposure.
... MDA is one of the most important products of membrane lipid peroxidation, and its production can aggravate cell membrane damage. Therefore, MDA is a commonly used indicator of lipid peroxidation, which indirectly determines the degree to which ferroptosis occurs, and detection of the expression level of MDA reflected the degree of membrane lipid peroxidation in many studies 32,33 . Our results also suggested that MDA expression levels were significantly increased in the CDDP and CDDP + PBS groups and that this level decreased after VE treatment. ...
Ferroptosis is widely present in fibrosis-related diseases. The basic pathology of premature ovarian insufficiency (POI) involves ovarian tissue fibrosis, and there are currently fewer relevant studies addressing the association between ferroptosis and POI. This study aimed to demonstrate that ferroptosis induced by cisplatin (CDDP) caused ovarian tissue fibrosis, leading to POI. Vitamin E (VE), a ferroptosis inhibitor, could repair damaged ovarian function. CDDP was used to establish a rat model of POI, and VE was administered to reverse the reproductive toxicity of CDDP. Ovarian function was assessed by histological section staining, follicle counts, sex hormone levels, as well as fertility assays. The extent of ferroptosis was assessed by transmission electron microscopy (TEM), malondialdehyde (MDA), Perls staining. CCK-8, Ethynyl-2-Deoxyuridine (EdU), and scratch assays were used to determine the effect of CDDP and VE on ovarian granulosa cell (GC) viability. Western blot, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were performed to evaluate ferroptosis-related molecular changes. Our results showed that CDDP caused follicle development disorders and ovarian tissue fibrosis, the levels of sex hormones suggested impaired ovarian function, and VE could reverse the reproductive toxicity of CDDP. The results of TEM, MDA and Perls staining suggested that the typical mitochondrial signature of ferroptosis was altered in ovarian GCs from the CDDP group, with significantly higher levels of lipid peroxidation and significant iron deposition in ovarian tissue, whereas VE mitigated the extent of ferroptosis. Molecular experiments then confirmed that the ferroptosis-related molecules acetyl CoA synthetase long chain family member 4 (ACSl4), 15-lipoxygenase-1 (ALOX15), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) were differentially expressed in each group. In summary, our study preliminarily demonstrated that CDDP may promote GCs to undergo ferroptosis, cause follicle development disorders, ovarian tissue fibrosis, and induce POI by regulating the expression of ACSl4, ALOX15, SLC7A11, and GPX4, while VE improved impaired ovarian function.
As a life‐threatening disease, acute lung injury (ALI) may progress to chronic pulmonary fibrosis. For the treatment of lung injury, Tempol is a superoxide dismutase mimetic and intracellular redox agent that can be a potential drug. This study investigated the regulatory mechanism of Tempol in the treatment of ALI. A mouse model of ALI was established, and HE staining was used to examine histomorphology. The CCK‐8 assay was used to measure cell viability, and oxidative stress was assessed by corresponding kits. Flow cytometry and dichlorodihydrofluorescein diacetate staining assays were used to detect reactive oxygen species (ROS) levels. Protein expression levels were measured by Western blot analysis and ELISA. Pulmonary vascular permeability was used to measure the lung wet/dry weight ratio. The level of oxidative stress was increased in ALI mice, and the level of ferroptosis was upregulated. Tempol inhibited this effect and alleviated ALI. The administration of Tempol alleviated the pathological changes in ALI, inhibited pulmonary vascular permeability, and improved lung injury in ALI mice. The upregulation of genes essential for glutathione (GSH) metabolism induced by lipopolysaccharide (LPS) was inhibited by Tempol. In addition, nuclear factor‐related factor 2 (Nrf2) is activated by Tempol therapy to regulate the de novo synthesis pathway of GSH, thereby alleviating LPS‐induced lung epithelial cell damage. The results showed that Tempol alleviated ALI by activating the Nrf2 pathway to inhibit oxidative stress and ferroptosis in lung epithelial cells. In conclusion, this study demonstrates that Tempol alleviates ALI by inhibiting ferroptosis in lung epithelial cells through the effect of Nrf2 on GSH synthesis.
