Protective Effects of Dexazoxane on Rat Ferroptosis in Doxorubicin-Induced Cardiomyopathy Through Regulating HMGB1

Frontiers in Cardiovascular Medicine, Journal Year: 2021, Volume and Issue: 8

Published: July 14, 2021

Dexrazoxane (DXZ) reduces cytotoxicity caused by Doxorubicin (DOX). However, the mechanism of DXZ in ferroptosis and cardiomyopathy remains unclear. This research, therefore, explores role DOX-induced rats. Kaplan–Meier survival analysis was performed rats treated DOX combination with inhibitor (FER-1) or other cell death–associated inhibitors. The ferroptosis, cardiotoxicity, expression high mobility group box 1 (HMGB1) FER-1 were determined hematoxylin eosin staining, echocardiographic analysis, quantitative real-time PCR. DOX-treated that received HMGB1 knockdown overexpression further detected using molecular experiments. Finally, viability, level malondialdehyde (MDA), expressions ferroptosis-related markers (PTGS2, GPX4, FTH1) rat cardiomyocyte H9c2 exposed to combined FER-1, zVAD (an apoptosis inhibitor), DXZ, not performing increased induced DOX. cardiotoxicity could be reversed DXZ. but inhibited FER-1. Overexpression promoted although silencing showed opposite effects. data indicate suppressed viability MDA cells a dose-dependent manner. Moreover, increase PTGS2 decrease GPX4 FTH1 Therefore, has protective effects on through regulating HMGB1.

Language: Английский

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Platycodin D regulates high glucose-induced ferroptosis of HK-2 cells through glutathione peroxidase 4 (GPX4)

Bioengineered, Journal Year: 2022, Volume and Issue: 13(3), P. 6627 - 6637

Published: Feb. 28, 2022

Diabetic nephropathy (DN) is associated with inflammation. Platycodin D (PD) demonstrates anti-inflammatory activity. However, whether PD affects DN remains to be explored. Here, we aimed discuss the role of in and its underlying mechanisms. High glucose (HG)-induced HK-2 cells were treated PD, cell viability was assessed using Thiazolyl Blue Tetrazolium Bromide (MTT) assay. Ferroptosis-related factors such as lactate dehydrogenase (LDH) activity, lipid reactive oxygen species (ROS), iron (Fe2+) level, GSH malondialdehyde (MDA) level evaluated. Cell death evaluated TUNEL GPX4 expression Quantitative Real-time PCR (qRT-PCR) Western blotting analysis. The results indicated that HG increased LDH ROS production, Fe2+ levels, MDA levels decreased suggesting condition induced ferroptosis. treatment inhibited ferroptosis HG-induced cells, downregulated ACSL4 TFR1 expression, upregulated FTH-1 SLC7A11 expression. reversed effects on death. Moreover, HG-stimulated cells. Furthermore, substantiated suppressed by modulating In conclusion, upregulating may an effective drug for clinical DN.

Language: Английский

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Ferroptosis and its role in cardiomyopathy

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 153, P. 113279 - 113279

Published: June 20, 2022

Heart disease is the leading cause of death worldwide. Cardiomyopathy a characterized by heart muscle damage, resulting in structurally and functionally change, as well failure sudden cardiac death. The key pathogenic factor cardiomyopathy loss cardiomyocytes, but related molecular mechanisms remain unclear. Ferroptosis newly discovered regulated form cell death, iron accumulation lipid peroxidation during Recent studies have shown that ferroptosis plays an important regulatory roles occurrence development many diseases such myocardial ischemia/reperfusion injury, failure. However, systemic association remains largely unknown needs to be elucidated. In this review, we provide overview its role individual cardiomyopathies, highlight targeting maybe potential therapeutic strategy for therapy future.

Language: Английский

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Caveolin‐1 promotes cancer progression via inhibiting ferroptosis in head and neck squamous cell carcinoma

Journal of Oral Pathology and Medicine, Journal Year: 2021, Volume and Issue: 51(1), P. 52 - 62

Published: Dec. 7, 2021

Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease worldwide. Much progress has been made in exploring mechanisms improving the therapy of HNSCC, but only a few studies have focused on role ferroptosis HNSCC progression. The current study aimed to reveal underlining that caveolin-1 (CAV1)-ROS (reactive oxygen species)-ferroptosis axis affect process discover novo therapeutic targets or strategies.The CAV1 was analyzed by FerrDb, its clinical significance examined TCGA dataset HNSCC. expressions (CAV1) tissues were measured immunohistochemistry, western blot, real-time PCR assay. Three siRNA sequences designed silence mRNA cells. Cell proliferation, colony formation, wound-healing, transwell assays used examine migration, invasion cancer ROS evaluation intracellular Fe2+ content performed levels ferroptosis.Through analysis with published data, found overexpress than normal tissues, one vital suppressors pathway. Our showed over expressed high level predicted poorer prognosis. Further experiments indicated could inhibit cells promote migration invasion.Overexpression inhibited ferroptosis, leading phenotypes, as well worse regulatory pathway are potential for designing diagnostic combined strategies patients.

Language: Английский

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Abnormal Iron and Lipid Metabolism Mediated Ferroptosis in Kidney Diseases and Its Therapeutic Potential

Metabolites, Journal Year: 2022, Volume and Issue: 12(1), P. 58 - 58

Published: Jan. 10, 2022

Ferroptosis is a newly identified form of regulated cell death driven by iron-dependent phospholipid peroxidation and oxidative stress. has distinct biological morphology characteristics, such as shrunken mitochondria when compared to other known deaths. The regulation ferroptosis includes different molecular mechanisms multiple cellular metabolic pathways, including glutathione/glutathione peroxidase 4(GPX4) signaling which are involved in the amino acid metabolism activation GPX4; iron import/export storage/release intracellular through iron-regulatory proteins (IRPs), lipid unsaturated fatty acids membranes. plays an essential role pathology various kidneys diseases, acute kidney injury (AKI), chronic disease (CKD), autosomal dominant polycystic (ADPKD), renal carcinoma (RCC). Targeting with its inducers/initiators inhibitors can modulate progression diseases animal models. In this review, we discuss characteristics ferroptosis-based mechanisms, highlighting potential main ferroptosis-associated pathways treatment prevention diseases.

Language: Английский

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Extracellular CIRP Promotes GPX4-Mediated Ferroptosis in Sepsis

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: June 29, 2022

Sepsis is characterized by life-threatening organ dysfunction caused a dysregulated host response to infection. Extracellular cold-inducible RNA-binding protein (eCIRP) damage-associated molecular pattern (DAMP) that promotes inflammation and induces cell death via apoptosis, NETosis, and/or pyroptosis. Ferroptosis form of regulated the accumulation lipid peroxide on cellular membranes. We hypothesize eCIRP ferroptosis in macrophages lung tissue during sepsis. RAW 264.7 cells stimulated with recombinant murine (rm) CIRP significantly decreased expression glutathione peroxidase 4 (GPX4), negative regulator ferroptosis, increased reactive oxygen species (ROS) TLR4 dependent manner. In TLR4-/- peritoneal macrophages, depression GPX4 increase ROS levels were attenuated after rmCIRP-treatment compared WT macrophages. rmCIRP also induced which was corrected inhibitor, ferrostatin-1 (Fer-1). Intraperitoneal injection tissue, whereas reduced Fer-1 treatment. decreased, while malondialdehyde (MDA), iron levels, injury scores lungs mice cecal ligation puncture (CLP)-induced sepsis CIRP-/- mice. Treatment C23, specific CLP alleviated decrease MDA tissue. These findings suggest septic decreasing increasing ROS. Therefore, regulation targeting may provide new therapeutic approach other inflammatory diseases.

Language: Английский

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Emerging significance and therapeutic targets of ferroptosis: a potential avenue for human kidney diseases

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(9)

Published: Sept. 22, 2023

Abstract Kidney diseases remain one of the leading causes human death and have placed a heavy burden on medical system. Regulated cell contributes to pathology plethora renal diseases. Recently, with in-depth studies into kidney death, new iron-dependent modality, known as ferroptosis, has been identified attracted considerable attention among researchers in pathogenesis therapeutics treat them. The majority suggest that ferroptosis plays an important role pathologies multiple diseases, such acute injury (AKI), chronic disease, carcinoma. In this review, we summarize recently regulatory molecular mechanisms discuss pathways action various describe protective effect inhibitors against especially AKI. By summarizing prominent roles different progress made studying provide directions strategies for future research summary, ferroptotic factors are potential targets therapeutic intervention alleviate targeting them may lead treatments patients

Language: Английский

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Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: April 28, 2023

Cellular senescence describes a state of permanent proliferative arrest in cells. Studies have demonstrated that diabetes promotes the pathological accumulation senescent cells, which turn impairs cell movement and proliferation. Historically, has been perceived to be detrimental consequence chronic wound healing. However, underlying mechanism causes cells remain diabetic wounds is yet elucidated. Ferroptosis ferritinophagy observed are due iron metabolism disorders, directly associated with initiation progression diabetes. Herein, we reveal fibroblasts resistant ferroptosis impaired may contributing cause. Further, expression NCOA4, key factor influences ferritinophagy, decreased both tissue high glucose-induced fibroblasts. Moreover, NCOA4 overexpression could render more vulnerable ferroptosis. A faster healing process was also linked induction Thus, resistance impedes removal fibroblasts; promoting reverse this process, significant implications for management wounds.

Language: Английский

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Ferroptosis in acute kidney injury following crush syndrome: A novel target for treatment

Journal of Advanced Research, Journal Year: 2023, Volume and Issue: 54, P. 211 - 222

Published: Jan. 23, 2023

Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia acute kidney (AKI). Especially AKI, it the leading cause death from CS. There are various cell forms in among which ferroptosis typical form death. However, role has not been fully revealed CS-AKI. This review aimed to summarize evidence CS-AKI its related molecular mechanism, discuss therapeutic significance CS-AKI, open up new ideas for treatment One main pathological manifestations renal tubular epithelial dysfunction death, attributed massive deposition myoglobin. Large amounts myoglobin released damaged muscle deposited tubules, impeding normal tubules function directly damaging with oxidative stress elevated iron levels. Lipid peroxidation damage overload distinguishing features ferroptosis. Moreover, high levels pro-inflammatory cytokines damage-associated molecule pattern molecules (HMGB1, double-strand DNA, macrophage extracellular trap) tissue have shown promote how occurs whether can be target remains unclear. In our current work, we systematically reviewed occurrence underlying mechanism

Language: Английский

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Cytoplasmic HMGB1 induces renal tubular ferroptosis after ischemia/reperfusion

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 116, P. 109757 - 109757

Published: Feb. 1, 2023

As a damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1) is well-studied and released from injured tubular epithelial cells to trigger cell death. However, the role of intracellular HMGB1 induced death during acute kidney injury (AKI) poorly understood. We showed that cytosolic ferroptosis by binding acyl-CoA synthetase long-chain family member 4 (ACSL4), driver ferroptosis, following renal ischemia/reperfusion (I/R). Both mouse human kidneys with were characterized nucleocytoplasmic translocation HMGB1in cells. Pharmacological inhibition deletion in mice inhibited I/R-induced AKI, inflammation compared those controls. Co-immunoprecipitation serial section staining confirmed interaction between ACSL4. Taken together, our results demonstrated cytoplasmic essential for exacerbating inflammation-associated cellular activating via ACSL4 after I/R injury. These findings indicate regulator promising therapeutic target AKI.

Language: Английский

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