Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 12

Published: Feb. 22, 2022

Doxorubicin (DOX) is an anthracycline antibiotic that used extensively for the management of carcinoma; however, its clinical application limited due to serious cardiotoxic side effects. Ferroptosis represents iron-dependent and reactive oxygen species (ROS)-related cell death has been proven contribute progression DOX-induced cardiomyopathy. Fisetin a natural flavonoid abundantly present in fruits vegetables. It reported exert cardioprotective effects against cardiotoxicity experimental rats. However, underlying mechanisms remain unknown. The study investigated role fisetin molecular mechanism through experiments cardiomyopathy rat H9c2 models. results revealed treatment could markedly abate by alleviating cardiac dysfunction, ameliorating myocardial fibrosis, mitigating hypertrophy rats, attenuating ferroptosis cardiomyocytes reversing decline GPX4 level. Mechanistically, exerted antioxidant effect reducing MDA lipid ROS levels increasing glutathione (GSH) Moreover, protective SIRT1 expression Nrf2 mRNA protein nuclear translocation, which resulted activation downstream genes such as HO-1 FTH1. Selective inhibition attenuated cells, turn decreased GSH levels, well Nrf2, HO-1, FTH1 expressions. In conclusion, exerts therapeutic inhibiting via SIRT1/Nrf2 signaling pathway activation.

Language: Английский

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Nrf2 attenuates ferroptosis-mediated IIR-ALI by modulating TERT and SLC7A11

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(11)

Published: Oct. 29, 2021

Abstract Acute lung injury (ALI) carries a mortality rate of ~50% and is hot topic in the world critical illness research. Nuclear factor erythroid 2-related 2 (Nrf2) modulator intracellular oxidative homeostasis serves as an antioxidant. The Nrf2-related anti-oxidative stress strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), catalytic portion protein, reported to travel mitochondria alleviate ROS. In our study, we found that TERT was significantly reduced tissue Nrf2 −/− mice model intestinal ischemia/reperfusion-induced acute (IIR-ALI). addition, MDA levels showed marked increase, whereas GSH GPX4 fell drastically ALI models. Moreover, typical-related structural changes were observed type II alveolar epithelial cells IIR model. We further employed scanning transmission X-ray microscopy (STXM) examine Fe distribution within cells. Based on observations, massive aggregates MLE-12 upon OGD/R (oxygen glucose deprivation/reperfusion) induction. Additionally, silencing dramatically SLC7A11 levels, exacerbated cellular injuries. contrast, TERT-overexpressing exhibited elevation thereby inhibited ferroptosis. Collectively, these data suggest can negatively regulate via modulation levels. conclusion from this study brings insight into new candidates be targeted future IIR-ALI therapy.

Language: Английский

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The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review

Annals of Translational Medicine, Journal Year: 2022, Volume and Issue: 10(6), P. 368 - 368

Published: March 1, 2022

Background and Objective: Ferroptosis is a recently discovered form of cell death which differs from other forms in terms morphology, biochemistry, regulatory mechanisms. regulated by complex system the precise molecular mechanisms are still being elucidated. Over past few years, extensive research has revealed that essence ferroptosis iron-dependent accumulation lipid hydroperoxides induced oxidative stress, System Xc-glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway main prevention system. Meanwhile, antioxidant systems have also been implicated regulating ferroptosis, including transsulfuration pathway, mevalonate inhibitory protein 1 (FSP1)-Coenzyme Q10 (CoQ10) dihydroorotate dehydrogenase (DHODH)-dihydroubiquione (CoQH2) GTP cyclohydrolase-1 (GCH1)-tetrahydrobiopterin (BH4) pathway. This article reviews its critical role systems, aiming to reveal antioxidation an important method inhibiting provide new direction for treatment ferroptosis-related diseases. Methods: We searched all original papers about using PubMed November 2021. The search used included: ‘ferroptosis’, ‘ferroptosis inducers’, inhibitors’, GSH’, GPX4’, Xc-’, ‘SLC7A11’, ‘P53’, ‘NRF2 ferroptosis’, ‘iron metabolism’, ‘lipid peroxidation’, ‘antioxidant systems’, ‘transsulfuration pathway’, ‘mevalonate ‘FSP1-CoQ10’, ‘DHODH-CoQH2’, ‘GCH1-BH4’. Key Content Findings: first introduced origin common inhibitors inducers. Next, we discussed existing studies. Finally, briefly summarized relationship between It reveals ferroptosis. Conclusions: review discusses recent rapid progress understanding several systems.

Language: Английский

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Nanoparticle-induced ferroptosis: detection methods, mechanisms and applications

Nanoscale, Journal Year: 2021, Volume and Issue: 13(4), P. 2266 - 2285

Published: Jan. 1, 2021

Although ferroptosis is an iron-dependent cell death mechanism involved in the development of some severe diseases (e.g., Parkinsonian syndrome, stroke and tumours), combination nanotechnology with for treatment these has attracted substantial research interest. However, it challenging to differentiate nanoparticle-induced from other types deaths apoptosis, pyroptosis, necrosis), elucidate detailed mechanisms identify key property nanoparticles responsible ferroptotic deaths. Therefore, a summary aspects current on nano-ferroptosis important timely. In this review, we endeavour summarize convincing techniques that can be employed specifically examine Then, discuss molecular initiating events nanosized inducers cascade signals cells, therefore elaborate mechanisms. Besides, physicochemical properties nano-inducers are also discussed acquire fundamental understanding nano-structure-activity relationships (nano-SARs) ferroptosis, which may facilitate design nanomaterials deliberately tune ferroptosis. Finally, future perspectives its applications provided.

Language: Английский

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β-Caryophyllene suppresses ferroptosis induced by cerebral ischemia reperfusion via activation of the NRF2/HO-1 signaling pathway in MCAO/R rats

Phytomedicine, Journal Year: 2022, Volume and Issue: 102, P. 154112 - 154112

Published: April 22, 2022

Language: Английский

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Interleukin-6 promotes ferroptosis in bronchial epithelial cells by inducing reactive oxygen species-dependent lipid peroxidation and disrupting iron homeostasis

Bioengineered, Journal Year: 2021, Volume and Issue: 12(1), P. 5279 - 5288

Published: Jan. 1, 2021

Asthma occurs accompanied by the ferroptosis in bronchial epithelial cells, during which Interleukin-6 (IL-6) plays a key role. However, associations between IL-6, and asthma have not been reported. Bronchial cells BEAS-2B were induced different concentrations of IL-6 cell viability was detected MTT assay. The TBARS production rate corresponding kit. expression oxidative stress-related indexes ELISA. Iron Assay Kits total iron levels ferrous ion (Fe2+) levels. Labile pool assay used to detect unstable pool. ferroptosis-related proteins Western blot. To further examine mechanism action, inhibitor Ferrostatin 1 (Fer-1), antioxidant NAC, supplement Fe added. We found that decreased activity, promoted lipid peroxidation, disrupted homeostasis death cells. pretreatment with Ferrostatin-1 (Fer-1) NAC partially reversed effect on peroxidation while augmented effect. Overall, promotes inducing reactive oxygen species (ROS)-dependent disrupting homeostasis.

Language: Английский

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Ferroptosis: regulation by competition between NRF2 and BACH1 and propagation of the death signal

FEBS Journal, Journal Year: 2022, Volume and Issue: 290(7), P. 1688 - 1704

Published: Feb. 2, 2022

Ferroptosis is triggered by a chain of intracellular labile iron-dependent peroxidation cell membrane phospholipids. important not only as cause ischaemic and neurodegenerative diseases but also mechanism cancer suppression, better understanding its regulatory required. It has become clear that ferroptosis finely controlled two oxidative stress-responsive transcription factors, NRF2 (NF-E2-related factor 2) BACH1 (BTB CNC homology 1). inhibit promote ferroptosis, respectively, activating or suppressing the expression genes in major pathways ferroptosis: iron metabolism, GSH (glutathione) -GPX4 (glutathione peroxidase 4) pathway FSP1 (ferroptosis suppressor protein 1)-CoQ (coenzyme Q) pathway. In addition to this, control through regulation lipid metabolism differentiation. This multifaceted considered have been acquired during evolution multicellular organisms, allowing utilization for maintaining homeostasis, including suppression. terms cell-cell interaction, it revealed property propagating surrounding cells along with peroxidation. The propagation phenomenon could be used realize anticancer therapy future. this review, these points will summarized discussed.

Language: Английский

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Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses

Cellular & Molecular Biology Letters, Journal Year: 2022, Volume and Issue: 27(1)

Published: March 19, 2022

Acute lung injury (ALI) has received considerable attention in the field of intensive care as it is associated with a high mortality rate. Obacunone (OB), widely found citrus fruits, natural bioactive compound anti-inflammatory and antioxidant activities. However, not clear whether OB protects against lipopolysaccharide (LPS)-induced ALI. Therefore, this study, we aimed to evaluate protective effects potential mechanisms LPS-induced ALI BEAS-2B cell injury.We established model mouse by treating LPS. Samples vitro were subjected death, Cell Counting Kit-8, lactate dehydrogenase (LDH) release assays. The total number cells neutrophils, protein content, levels IL-6, TNF-α, IL-1β determined bronchoalveolar lavage fluid (BALF). Glutathione, reactive oxygen species, malondialdehyde tissue. Additionally, immunohistochemical analysis, immunofluorescence, western blot, quantitative real-time PCR, enzyme-linked immunosorbent assay conducted examine OB. Furthermore, mice treated an Nrf2 inhibitor (ML385) verify its role ferroptosis. Data analyzed using one-way analysis variance or paired t-tests.Compared LPS group, effectively alleviated decreasing wet/dry weight ratio, species production, superoxide dismutase glutathione consumption vivo. In addition, significantly histopathological injury, reduced inflammatory cytokine secretion Fe2+ 4-HNE levels, upregulated GPX4, SLC7A11, expression. Mechanistically, activated inhibiting ubiquitinated proteasome degradation. ML385 reversed ALI.Overall, alleviates ALI, making novel agent

Language: Английский

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Astragaloside IV regulates the ferroptosis signaling pathway via the Nrf2/SLC7A11/GPX4 axis to inhibit PM2.5-mediated lung injury in mice

International Immunopharmacology, Journal Year: 2022, Volume and Issue: 112, P. 109186 - 109186

Published: Sept. 15, 2022

Language: Английский

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Melatonin attenuates LPS-induced pyroptosis in acute lung injury by inhibiting NLRP3-GSDMD pathway via activating Nrf2/HO-1 signaling axis

International Immunopharmacology, Journal Year: 2022, Volume and Issue: 109, P. 108782 - 108782

Published: April 23, 2022

Language: Английский

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