Ferroptosis is newly characterized form of neuronal cell death in response to arsenite exposure

Tang, Qianghu; Bai, Lulu; Zou, Zhen; Pan, Meng; Xia, Yinyin; Cheng, Shuqun; Mu, Shaoyu; Zhou, Jianrong; Wang, Xuefeng; Qin, Xia; Cao, Xin; Jiang, Xuejun; Chen, Chengzhi

doi:10.1016/j.neuro.2018.04.012

Cited by 69 publications

(38 citation statements)

References 34 publications

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“…Finally, ferroptosis may be involved in the toxic effects of environmental contaminants. A recent report found that mice fed arsenite in their drinking water exhibited increased neuronal ferroptosis [ 10 ]. Thus, ferroptosis markers may aid in detecting individuals exposed to arsenite in their drinking water, and ferroptosis inhibitors might be useful for such communities.…”

Section: Introductionmentioning

confidence: 99%

Unsolved mysteries: How does lipid peroxidation cause ferroptosis?

2018

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Ferroptosis is a cell death process driven by damage to cell membranes and linked to numerous human diseases. Ferroptosis is caused by loss of activity of the key enzyme that is tasked with repairing oxidative damage to cell membranes—glutathione peroxidase 4 (GPX4). GPX4 normally removes the dangerous products of iron-dependent lipid peroxidation, protecting cell membranes from this type of damage; when GPX4 fails, ferroptosis ensues. Ferroptosis is distinct from apoptosis, necroptosis, necrosis, and other modes of cell death. Several key mysteries regarding how cells die during ferroptosis remain unsolved. First, the drivers of lipid peroxidation are not yet clear. Second, the subcellular location of lethal lipid peroxides remains an outstanding question. Finally, how exactly lipid peroxidation leads to cell death is an unsolved mystery. Answers to these questions will provide insights into the mechanisms of ferroptotic cell death and associated human diseases, as well as new therapeutic strategies for such diseases.

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Section: Introductionmentioning

confidence: 99%

Unsolved mysteries: How does lipid peroxidation cause ferroptosis?

2018

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“…The pathological changes of cerebral cortex tissues tissue were evaluated by hematoxylin–eosin (H&E) staining according to protocols described previously. 4 Briefly, the tissue-containing slides were deparaffinized in xylene and dehydrated with ethanol. After staining with hematoxylin at room temperature, the sections were rinsed with distilled water and then stained with eosin.…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescence assay was conducted according to the protocols described previously. 4 Briefly, the tissue-containing slides were rinsed and incubated in the blocking solution containing serum. The sections were incubated with the primary anti-NeuN (1:500), anti-MAP2 (1:500) and anti-Ki67 (1:500) antibodies at 4 °C overnight.…”

Section: Methodsmentioning

confidence: 99%

“…The ultrastructure of mitochondria was observed by transmission electron microscopy as described previously. 4 Briefly, the cerebral cortex tissues were rapidly collected by heart perfusion-fixed technique with 4% paraformaldehyde and 2.5% (w/v) glutaraldehyde buffer. Afterwards, the tissues were dissected and cut into 1 mm 3 in size.…”

Section: Methodsmentioning

confidence: 99%

“…2 Previous investigations have demonstrated that ferroptosis can be triggered by natural stimuli, synthetic agents and environmental toxicants in many types of cells. 2 – 4 Intriguingly, the studies also reported that the engineered nanoparticles could cause ferroptotic cell death in mouse xenograft tumors, and thus suppressed the growth of tumors. 5 , 6 These findings suggest that nanoparticles are capable of inducing ferroptosis in animals and/or cultured cells.…”

Section: Introductionmentioning

confidence: 99%

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<p>Zinc Oxide Nanoparticles Induce Ferroptotic Neuronal Cell Death in vitro and in vivo</p>

Qin

Tang

Jiang

et al. 2020

IJN

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Purpose Zinc oxide nanoparticles (ZnONPs) are one of the most important nanomaterials that are widely used in the food, cosmetic and medical industries. Humans are often exposed to ZnONPs via inhalation, and they may reach the brain where neurotoxic effects could occur via systemic distribution. However, the mechanisms underlying how ZnONPs produce neurotoxic effects in the brain remain unclear. In this study, we aimed to investigate the novel mechanism involved in ZnONPs-induced neurotoxicity. Methods and Results We demonstrated for the first time that pulmonary exposure to ZnONPs by intratracheal instillation could trigger ferroptosis, a new form of cell death, in the neuronal cells of mouse cerebral cortex. A similar phenomenon was also observed in cultured neuron-like PC-12 cell line. By using a specific inhibitor of ferroptosis ferrostatin-1 (Fer-1), our results showed that inhibition of ferroptosis by Fer-1 could significantly alleviate the ZnONPs-induced neuronal cell death both in vivo and in vitro. Mechanistic investigation revealed that ZnONPs selectively activated the JNK pathway and thus resulted in the ferroptotic phenotypes, JNK inhibitor SP600125 could reverse lipid peroxidation upregulation and ferroptotic cell death induced by ZnONPs in PC-12 cells. Conclusion Taken together, this study not only demonstrates that pulmonary exposure of ZnONPs can induce JNK-involved ferroptotic cell death in mouse cortex and PC-12 cells, but also provides a clue that inhibition of ferroptosis by specific agents or drugs may serve as a feasible approach for reducing the untreatable neurotoxicity induced by ZnONPs.

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Realgar‐induced nephrotoxicity via ferroptosis in mice

Zhang

Cao

Zhou

et al. 2022

J of Applied Toxicology

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Ferroptosis is a novel form of iron-dependent cell death that is involved in arsenicinduced toxicity. Realgar is an arsenic-containing Chinese medicine, which can result in nephrotoxicity because of long-term exposure. However, it remains scientifically unknown whether Realgar is an inducer of ferroptosis in the kidney. This study investigated the role of ferroptosis in Realgar-induced kidney toxicity in mice. ICR mice were exposed to Realgar for 28 days, and HK2 cells were exposed to Realgar in the presence or absence of treatment with ferrostatin-1, a ferroptosis inhibitor. The ferroptosis-related indicators were further evaluated. Realgar can cause nephrotoxicity in mice by continuous gavage for 28 days, accompanied by an increase in iron accumulation and reactive oxygen species (ROS). The reduced expression of Slc7A11 and Gpx4 further confirmed the ferroptosis mediated by Realgar. Meanwhile, Realgar disrupted the antioxidant system as evidenced by the formation of ROS leading to the inactivation of antioxidant enzymes. Realgar caused ferroptosis in a dosedependent manner, which was significantly reduced by ferrostatin-1 in HK2 cells.This study revealed that Realgar-induced ferroptosis triggered nephrotoxicity in mice and provided new clues to elucidate the mechanism of Realgar-induced nephrotoxicity.

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Ferroptosis is newly characterized form of neuronal cell death in response to arsenite exposure

Cited by 69 publications

References 34 publications

Unsolved mysteries: How does lipid peroxidation cause ferroptosis?

Unsolved mysteries: How does lipid peroxidation cause ferroptosis?

<p>Zinc Oxide Nanoparticles Induce Ferroptotic Neuronal Cell Death in vitro and in vivo</p>

Realgar‐induced nephrotoxicity via ferroptosis in mice

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