Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(5), P. 315 - 336

Published: March 15, 2023

Language: Английский

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Ferrostatin-1 alleviates lipopolysaccharide-induced cardiac dysfunction

Bioengineered, Journal Year: 2021, Volume and Issue: 12(2), P. 9367 - 9376

Published: Nov. 17, 2021

Cardiac dysfunction is a common complication of sepsis, and attributed to severe inflammatory responses. Ferroptosis reported be involved in sepsis-induced cardiac inflammation. Therefore, we speculated that ferrostatin-1 (Fer-1), ferroptosis inhibitor, improves caused by sepsis. An intraperitoneal injection lipopolysaccharide (LPS) was performed induce rat model. Echocardiography, histopathology, biochemical western blot results were analyzed. Twelve hours after the LPS injection, LPS-treated rats exhibited deteriorating systolic function, increased levels injury markers prostaglandin endoperoxide synthase 2 (PTGS2). Additionally, iron deposition myocardium, with downregulating ferroportin (FPN, SLC40A1) transferrin receptor (TfR)expression, upregulating ferritin light chain (FTL) heavy (FTH1) expression. Meanwhile, also lipid peroxidation heart decreasing expression glutathione peroxidase 4 (GPX4). Moreover, cytokines, such as tumor necrosis-alpha (TNF-α), interleukin-1 (IL-1β), interleukin-6 (IL-6), cell infiltration following challenge. Finally, abovementioned adverse effects relieved Fer-1 except for TfR Mechanistically, significantly reduced toll-like (TLR4), phospho-nuclear factor kappa B (NF-κB), phospho-inhibitor Bα (IκBα) rats. In summary, these findings imply improved at least partially via TLR4/NF-κB signaling pathway.

Language: Английский

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Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx

Journal of Advanced Research, Journal Year: 2022, Volume and Issue: 41, P. 63 - 75

Published: Jan. 11, 2022

Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive loading leads a catabolic response as well exaggerated death. Ferroptosis recently identified form during aging and degeneration. However, it's potential association remains be illustrated.To identify whether can cause ferroptosis. To explore the role overloading chondrocyte ferroptosis.Chondrocytes were collected from unloading zones cartilage patients osteoarthritis (OA), ferroptosis phenotype was analyzed through transmission electron microscope microarray. Moreover, relationship between OA by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice model cultured high strain stress. Furthermore, Piezo1 ion channel development explored using its inhibitor (GsMTx4) agonist (Yoda1). Additionally, calcium-free medium stress, tested.Human mouse experiments revealed that induce GPX4-associated Conditional GPX4 aggravated experimental process, while additional treatment suppressor protein (FSP-1) coenzyme Q10 (CoQ10) abated GPX4-CKO mice. In experiments, inhibition activity increased expression, attenuated reduced severity osteoarthritis. induced damage largely abolished blocking calcium influx medium.Our findings show induces activation subsequent chondrocytes, which might provide target for treatment.

Language: Английский

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The role of iron homeostasis in remodeling immune function and regulating inflammatory disease

Science Bulletin, Journal Year: 2021, Volume and Issue: 66(17), P. 1806 - 1816

Published: Feb. 7, 2021

The essential trace element iron regulates a wide range of biological processes in virtually all living organisms. Because both deficiency and overload can lead to various pathological conditions, homeostasis is tightly regulated, understanding this complex process will help pave the way developing new therapeutic strategies for inflammatory disease. In recent years, significant progress has been made with respect elucidating roles iron-related genes development maintenance immune system. Here, we review timing mechanisms by which systemic cellular metabolism are regulated during response infectious disease, host pathogen compete iron. We also discuss evidence implications that cells such as macrophages, T cells, B require sufficient amounts their proliferation mediating effector functions, serves co-factor toll-like receptor 4 (TLR4) signaling, mitochondrial respiration, posttranslational regulation, epigenetic modification. addition, targeting ferroptosis, and/or conferring protection against infection, controlling inflammation, improving efficacy immunotherapy.

Language: Английский

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Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression

Journal of Neuroinflammation, Journal Year: 2021, Volume and Issue: 18(1)

Published: Oct. 30, 2021

Many neurological diseases involve neuroinflammation, during which overproduction of cytokines by immune cells, especially microglia, can aggregate neuronal death. Ferroptosis is a recently discovered cell metabolism-related form death and RSL3 well-known inducer ferroptosis. Here, we aimed to investigate the effects in neuroinflammation sensitivity different type microglia macrophage ferroptosis.Here, used quantitative RT-PCR analysis ELISA analyze production proinflammatory cytokine macrophages after lipopolysaccharides (LPS) stimulation. We CCK8, LDH, flow cytometry evaluate RSL3-induced Western blot was test activation inflammatory signaling pathway knockdown efficiency. SiRNA-mediated interference conducted GPX4 or Nrf2 BV2 microglia. Intraperitoneal injection LPS performed systemic inflammation severity vivo conditions.We found that ferroptosis inhibited (LPS)-induced peritoneal (PMs) ferroptosis-independent manner, whereas ferroptosis-conditioned medium significantly triggered PMs. Different showed varied Mechanistically, induced protein expression inhibit RNA Polymerase II recruitment transcription start site genes repress transcription, protect cells from Furthermore, simultaneously Fer-1 ameliorated LPS-induced conditions.These data revealed role macrophages, identified as novel inhibitor inflammation, uncovered molecular regulation Thus, targeting using should consider both pro-ferroptosis effect anti-inflammation achieve optimal outcome.

Language: Английский

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