Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 28, 2022

Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting remains attractive approach for treating tumors. However, the influence regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme iron-sulfur (Fe-S) cluster biogenesis, colorectal cancer (CRC) remain elusive. Here, using vivo gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss NFS1 significantly enhanced sensitivity CRC cells to oxaliplatin. In vitro results showed deficiency synergizing oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, ferroptosis) by increasing intracellular levels reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress phosphorylation level serine residues NFS1, which prevented S293 phosphorylation-dependent manner during treatment. addition, high transcriptionally regulated MYC, was found tumor tissues poor survival hyposensitivity chemotherapy patients CRC. Overall, findings this study provided insights into underlying mechanisms identified inhibition as promising strategy improving outcome platinum-based treatment

Language: Английский

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Physiological and pharmacological modulation of BAX

Trends in Pharmacological Sciences, Journal Year: 2021, Volume and Issue: 43(3), P. 206 - 220

Published: Nov. 27, 2021

Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity permeabilizing the outer membrane (MOM). While physiological function BAX ensures tissue homeostasis, dysregulation leads to aberrant death. Despite being promising therapeutic target for human diseases, historically development drugs has focused on antiapoptotic BCL-2 proteins, due challenges in elucidating mechanism activation and identifying druggable surfaces BAX. Here, we discuss recent studies that have provided structure-function insights identified regulatory control activation. Moreover, emphasize small molecule orthosteric, allosteric, oligomerization modulators provide novel opportunities biological investigation progress towards drugging

Language: Английский

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Comprehensive Analysis of Cuproptosis-Related Genes in Immune Infiltration and Prognosis in Melanoma

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

Published: June 28, 2022

Skin cutaneous melanoma (SKCM, hereafter referred to as melanoma) is the most lethal skin cancer with increasing incidence. Regulated cell death plays an important role in tumorigenesis and serves target for almost all treatment strategies. Cuproptosis recently identified copper-dependent regulated form that relies on mitochondria respiration. However, its remains unknown. The correlation of cuproptosis-related genes tumor prognosis far be understood, either. In present study, we explored between by accessing analyzing a public database found 11 out 12 were upregulated tissues three (LIPT1, PDHA1, SLC31A1) have predictive value prognosis. subgroup patients higher gene expression showed longer overall survival than those lower expression. We chose LIPT1 further exploration. was increased biopsies independent favorable prognostic indicator patients. Moreover, positively correlated PD-L1 negatively associated Treg infiltration. after receiving immunotherapy, indicating LIPT1. Finally, pan-cancer analysis indicated differentially expressed diverse cancers compared normal multiple immune checkpoints, especially PD-L1. It could serve some types. conclusion, our study demonstrated genes, LIPT1, melanoma, revealed infiltration thus providing new clues assessment immunotherapy melanoma.

Language: Английский

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The emerging role of ferroptosis in intestinal disease

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(4)

Published: March 17, 2021

Ferroptosis is a newly recognised type of regulated cell death (RCD) characterised by iron-dependent accumulation lipid peroxidation. It significantly distinct from other RCDs at the morphological, biochemical, and genetic levels. Recent reports have implicated ferroptosis in multiple diseases, including neurological disorders, kidney injury, liver cancer. Ferroptotic has also been associated with dysfunction intestinal epithelium, which contributes to several diseases. Research on may provide new understanding disease pathogenesis that benefits clinical treatment. In this review, we an overview its underlying mechanisms, then describe emerging role ischaemia/reperfusion (I/R) inflammatory bowel (IBD), colorectal cancer (CRC).

Language: Английский

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Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis

Circulation, Journal Year: 2023, Volume and Issue: 147(19), P. 1444 - 1460

Published: March 29, 2023

Myocardial ischemia-reperfusion (I/R) injury causes cardiac dysfunction to myocardial cell loss and fibrosis. Prevention of death is important protect function after I/R injury. The process reperfusion can lead multiple types cardiomyocyte death, including necrosis, apoptosis, autophagy, ferroptosis. However, the time point at which various modes occur mechanisms underlying ferroptosis regulation in cardiomyocytes are still unclear.Using a left anterior descending coronary artery ligation mouse model, we sought investigate To discover key molecules involved ferroptosis, performed metabolomics study. Loss/gain-of-function approaches were used understand role 15-lipoxygenase (Alox15) peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) injury.We found that apoptosis necrosis occurred early phase injury, was predominant form during prolonged reperfusion. Metabolomic profiling eicosanoids revealed Alox15 metabolites accumulated ferroptotic cardiomyocytes. We demonstrated expression specifically increased injured area ventricle below suture colocalized with Furthermore, myocardial-specific knockout mice alleviated restored function. 15-Hydroperoxyeicosatetraenoic acid (15-HpETE), an intermediate metabolite derived from arachidonic by Alox15, identified as trigger for explored mechanism its effects 15-HpETE promoted binding Pgc1α ubiquitin ligase ring finger protein 34, leading ubiquitin-dependent degradation. Consequently, attenuated mitochondrial biogenesis abnormal morphology observed. ML351, specific inhibitor level Pgc1α, inhibited protected myocardium, caused recovery.Together, our results established Alox15/15-HpETE-mediated plays

Language: Английский

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Immune checkpoint inhibitor–associated myocarditis: manifestations and mechanisms

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(5)

Published: Feb. 28, 2021

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant lethal. The underlying basis myocarditis not completely understood. While importance T cells clear, inciting antigens, why they recognized, mechanisms leading to cardiac cell injury remain poorly characterized. issues underscore need for basic clinical studies define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, develop effective treatments. An improved understanding will provide insights into equilibrium between immune cardiovascular systems.

Language: Английский

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Ferroptosis in Cancer Treatment: Another Way to Rome

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Sept. 25, 2020

Ferroptosis is a newly described type of programmed cell death and intensively related to both maintaining homeostasis the development diseases, especially cancers. Inducing ferroptosis leads mitochondrial dysfunction toxic lipid peroxidation in cells, which plays pivotal role suppressing cancer growth progression. Here, we reviewed existing studies about molecular mechanisms involved different antitumor treatments, such as chemotherapy, targeted therapy, radiotherapy, immunotherapy. We focused particular on distinct combinatorial therapeutic effects synergistic sensitization effect drug-resistance reversal achieved when using inducers with conventional therapy. Finally, discussed challenges opportunities clinical applications ferroptosis. The application nanotechnolgy other novel technologies may provide new direction ferroptosis-driven therapies.

Language: Английский

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Myocardial ischemia/reperfusion injury: Mechanisms of injury and implications for management (Review)

Experimental and Therapeutic Medicine, Journal Year: 2022, Volume and Issue: 23(6)

Published: May 6, 2022

Myocardial infarction is one of the primary causes mortality in patients with coronary heart disease worldwide. Early treatment acute myocardial restores blood supply ischemic myocardium and decreases risk. However, when interrupted recovered within a certain period time, it more serious damage to original myocardium; this known as ischemia/reperfusion injury (MIRI). The pathophysiological mechanisms leading MIRI are associated oxidative stress, intracellular calcium overload, energy metabolism disorder, apoptosis, endoplasmic reticulum autophagy, pyroptosis, necroptosis ferroptosis. These interplay another directly or indirectly lead aggravation effect. In past, apoptosis autophagy have attracted attention but ferroptosis also serve key roles. mechanism has not been fully elucidated. present study reviews underlying MIRI. Based on current understanding MIRI, association between cell death‑associated signaling pathways were elaborated, providing direction for investigation novel targets clinical treatment.

Language: Английский

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Oxidative Stress and Antioxidant Treatments in Cardiovascular Diseases

Antioxidants, Journal Year: 2020, Volume and Issue: 9(12), P. 1292 - 1292

Published: Dec. 17, 2020

Oxidative stress plays a key role in many physiological and pathological conditions. The intracellular oxidative homeostasis is tightly regulated by the reactive oxygen species production defense mechanisms. Increased could alter lipid, DNA, protein, resulting cellular inflammation programmed cell death. Evidences show that an important progression of various cardiovascular diseases, such as atherosclerosis, heart failure, cardiac arrhythmia, ischemia-reperfusion injury. There are number therapeutic options to treat stress-associated diseases. Well known antioxidants, nutritional supplements, well more novel antioxidants have been studied. In addition, strategies using miRNA nanomedicine also being developed this article, we provide detailed description stress. Then, will introduce relationship between several Finally, focus on clinical implications

Language: Английский

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Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes

Redox Biology, Journal Year: 2021, Volume and Issue: 45, P. 102021 - 102021

Published: June 1, 2021

Ferroptosis is a programmed iron-dependent cell death associated with peroxidation of lipids particularly, phospholipids. Several studies suggested possible contribution mitochondria to ferroptosis although the mechanisms underlying mitochondria-mediated ferroptotic pathways remain elusive. Reduced glutathione (GSH) central player in that required for peroxidase 4 eliminate oxidized Mitochondria do not produce GSH, and transport GSH fully understood, two carrier proteins, dicarboxylate (DIC, SLC25A10) oxoglutarate (OGC, SLC25A11) have been participate transport. Here, we elucidated role DIC OGC as well mitochondrial bioenergetics H9c2 cardioblasts. Results showed are highly sensitive stimuli displaying fragmentation, lipid shortly after onset stimulus. Inhibition electron chain complexes oxidative phosphorylation worsened RSL3-induced ferroptosis. LC-MS/MS analysis revealed dramatic increase levels pro-ferroptotic oxygenated phosphatidylethanolamine species response RSL3 (ferroptosis inducer) cardiac ischemia-reperfusion. aggravated increased ROS, membrane depolarization, depletion. Dihydrolipoic acid, an essential cofactor several multienzyme complexes, attenuated induced direct reduction peroxidized phospholipids hydroxy-phospholipids vitro. In conclusion, suggest diminishes stimulates depletion inactivation leading

Language: Английский

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