Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 68, P. 100960 - 100960

Published: March 28, 2023

Pancreatic cancer continues to be one of the world's most lethal cancers. Chemotherapy resistance in patients with advanced pancreatic often accompany dismal prognosis, highlighting need investigate mechanisms drug and develop therapies overcome chemoresistance.This research was filed Chinese Clinical Trial Registry (ChiCTR2200061320). In order isolate primary normal fibroblasts (NFs) cancer-associated (CAFs) samples ductal adenocarcinoma (PDAC) paracancerous tissue from individuals diagnosed PDAC were obtained. The exosomes obtained using ultracentrifugation, their characteristics determined by Western blotting, nanoparticle tracking analysis, transmission electron microscopy. CAF-derived miRNAs analyzed RT-qPCR high-throughput sequencing. Gemcitabine (GEM) employed promote ferroptosis, ferroptosis levels monitoring lipid reactive oxygen species (ROS), cell survival, intracellular Fe2+ concentrations. To assess vivo tumor response GEM therapy, a xenograft mouse model utilized.Exosomes derived CAFs did not exhibit innate resistance. promoted chemoresistance cells following treatment secreting exosomes, maintaining signaling communication cells. Mechanistically, miR-3173-5p CAF sponged ACSL4 inhibited after uptake cells.This work demonstrates novel mode acquired identifies miR-3173-5p/ACSL4 pathway as promising target for GEM-resistant cancer.

Language: Английский

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Arachidonic acid metabolism in health and disease

MedComm, Journal Year: 2023, Volume and Issue: 4(5)

Published: Sept. 20, 2023

Arachidonic acid (AA), an n-6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays biochemical roles, as it the direct precursor bioactive lipid metabolites eicosanoids such prostaglandins, leukotrienes, epoxyeicosatrienoic obtained from three distinct enzymatic metabolic pathways: cyclooxygenase pathway, lipoxygenase cytochrome P450 pathway. metabolism involved not only in cell differentiation, tissue development, organ function but also progression diseases, hepatic fibrosis, neurodegeneration, obesity, diabetes, cancers. These are generally considered proinflammatory molecules, they trigger oxidative stress stimulate immune response. Therefore, interventions pathways effective ways to manage inflammatory-related diseases clinic. Currently, inhibitors targeting enzymes related important area drug discovery. Moreover, many advances have been made clinical studies combination with chemotherapy immunotherapy. Herein, we review discovery focus on relation health diseases. Furthermore, summarized, potential applications discussed.

Language: Английский

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Ferroptosis in lung cancer: a novel pathway regulating cell death and a promising target for drug therapy

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

Published: April 1, 2023

Lung cancer is a common malignant tumor that occurs in the human body and poses serious threat to health quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, radiotherapy. However, due strong metastatic characteristics lung emergence related drug resistance radiation resistance, overall survival rate patients not ideal. There an urgent need develop new strategies or effective drugs treat cancer. Ferroptosis, novel type programmed cell death, different from traditional death pathways such as apoptosis, necrosis, pyroptosis so on. It caused by increase iron-dependent reactive oxygen species intracellular iron overload, which leads accumulation lipid peroxides, thus inducing membrane oxidative damage, affecting normal life process cells, finally promoting ferroptosis. regulation ferroptosis closely physiological it involves metabolism, balance between oxygen-free radical reaction peroxidation. A large number studies have confirmed result combined action cellular oxidation/antioxidant system damage/repair, has great potential application therapy. Therefore, this review aims explore therapeutic targets for clarifying regulatory pathway Based on study ferroptosis, mechanism was understood chemical natural compounds targeting were summarized, with aim providing ideas In addition, also provides basis discovery clinical effectively

Language: Английский

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ACSL4-Mediated Ferroptosis and Its Potential Role in Central Nervous System Diseases and Injuries

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(12), P. 10021 - 10021

Published: June 12, 2023

As an iron-dependent regulated form of cell death, ferroptosis is characterized by lipid peroxidation and has been implicated in the occurrence development various diseases, including nervous system diseases injuries. Ferroptosis become a potential target for intervention these or injuries relevant preclinical models. member Acyl-CoA synthetase long-chain family (ACSLs) that can convert saturated unsaturated fatty acids, Acyl—CoA familymember4 (ACSL4) involved regulation arachidonic acid eicosapentaenoic acid, thus leading to ferroptosis. The underlying molecular mechanisms ACSL4-mediated will promote additional treatment strategies injury conditions. Our review article provides current view ferroptosis, mainly structure function ACSL4, as well role ACSL4 We also summarize latest research progress central further proving ACSL4-medicated important

Language: Английский

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ACSL4 promotes ferroptosis and M1 macrophage polarization to regulate the tumorigenesis of nasopharyngeal carcinoma

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 122, P. 110629 - 110629

Published: July 13, 2023

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor with high incidence recurrence rate. The crosstalk between ferroptosis tumor-associated macrophages (TAMs) thought to have major implications in interfering cancers. We intended explore the effect of acyl-CoA synthetase long-chain family member 4 (ACSL4) on pathogenesis NPC via TAMs.Differential genes patients were analyzed using publicly available databases, ferroptosis-related gene ACSL4 was identified. Expression cell lines xenografted mice examined. Colony formation, proliferation, migration, invasion assessed. abundance epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, Vimentin) confirmed. Lipid peroxidation levels related measured. Clophosome administered determine role TAMs mice.Low observed CNE-2 5-8F cells. Erastin (a inducer) increased lipid peroxidation, decreased viability, colony migration invasion, inhibited EMT. Moreover, promoted M2 M1 macrophage polarization. effects erastin additive. Ferrostatin-1, an inhibitor ferroptosis, exerted opposite reversed beneficial overexpression. In xenograft mice, clophosome hindered growth NPC, extra slightly enhanced antitumor ACSL4.Our findings indicated that at least through macrophages, providing potential direction for therapy.

Language: Английский

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Iron accumulation and lipid peroxidation: implication of ferroptosis in hepatocellular carcinoma

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 4, 2024

Ferroptosis is a type of controlled cell death caused by lipid peroxidation, which results in the rupture membrane. ferroptosis has been repeatedly demonstrated over past ten years to be significant factor number diseases. The liver iron storage organ, thus will have great potential treatment particularly prevalent HCC. In opening section this article, we give general summary pertinent molecular mechanisms, signaling pathways, and associated characteristics ferroptosis. primary regulating mechanisms during are then briefly discussed, conclude summarizing development novel therapeutic strategies used treat HCC recent years. crucial strategy for offers new perspectives on cancer.

Language: Английский

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Interplay between lipid dysregulation and ferroptosis in chondrocytes and the targeted therapy effect of metformin on osteoarthritis

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: April 1, 2024

Osteoarthritis (OA) is a devastating whole-joint disease affecting large population worldwide; the role of lipid dysregulation in OA and mechanisms underlying targeted therapy effect lipid-lowering metformin on remains poorly defined. To investigate effects progression to explore dysregulation-targeting treatment metformin. RNA-Seq data, biochemical, histochemical assays human murine cartilage as well primary chondrocytes were utilized determine dysregulation. Effects metformin, potent medication, ACSL4 expression chondrocyte metabolism determined. Further molecular experiments, including RT-qPCR, western blotting, flow cytometry, immunofluorescence staining, performed mechanisms. Mice with intra-articular injection ACLT-induced progression. 4-HNE expressions elevated mouse IL-1β-treated (P < 0.05). Ferrostatin-1 largely rescued IL-1β-induced MDA, peroxidation, ferroptotic mitochondrial morphology Metformin decreased levels OA-related genes 0.05) increased p-AMPK p-ACC chondrocytes. Intra-articular alleviated lesions mice, reverted percentage positive for MMP13, Col2a1, ACLT mice Ferroptotic promoted recruitment chemotaxis RAW264.7 cells via CCL2, which was blocked by vitro We establish critical polyunsaturated fatty acids metabolic process degradation define potential treatment. reshapes availability ameliorates ferroptosis sensitivity AMPK/ACC pathway. In future, gene-edited animals extensive omics technologies will be reveal detailed lipids' involvement lesions.

Language: Английский

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Qizhu Jianwei decoction triggers ferroptosis by exosome-mediated miR-199-3p/ACSL4 signaling pathways

Journal of Ethnopharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 119529 - 119529

Published: Feb. 1, 2025

Language: Английский

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ACSL4 promotes malignant progression of Hepatocellular carcinoma by targeting PAK2 transcription

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 224, P. 116206 - 116206

Published: April 12, 2024

Language: Английский

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Lutein Decreases Inflammation and Oxidative Stress and Prevents Iron Accumulation and Lipid Peroxidation at Glutamate-Induced Neurotoxicity

Antioxidants, Journal Year: 2022, Volume and Issue: 11(11), P. 2269 - 2269

Published: Nov. 17, 2022

The xanthophyll carotenoid lutein has been widely used as supplementation due to its protective effects in light-induced oxidative stress. Its antioxidant and anti-inflammatory features suggest that it a neuroprotective role well. Glutamate is major excitatory neurotransmitter the central nervous system (CNS), which plays key regulating brain function. Excess accumulation of intracellular glutamate accelerates an increase concentration reactive oxygen species (ROS) neurons leading neurotoxicity. In this study, we focused on SH-SY5Y neuroblastoma cells identify possible alterations stress, inflammation, iron metabolism affect neurological function itself presence lutein. First, ROS measurements were performed, then catalase (CAT) Superoxide Dismutase (SOD) enzyme activity determined by assay kits. ELISA technique was detect proinflammatory TNFα, IL-6, IL-8 cytokine secretions. Alterations uptake, storage, release followed gene expression Western blotting. Total level detections performed ferrozine-based detection method, heme kit for measurements. toward lipid-peroxidation RT-PCR. Our results show changes ROS, activity, modulate accumulation, may initiate lipid peroxidation cells. Meanwhile, attenuates glutamate-induced metabolism, peroxidation. According our findings, could be beneficial, supportive treatment neurodegenerative disorders.

Language: Английский

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