ALOX15-launched PUFA-phospholipids peroxidation increases the susceptibility of ferroptosis in ischemia-induced myocardial damage

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

Published: Aug. 15, 2022

Abstract Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by to cardiomyocytes leading various forms cell death. It believed that irreversible myocardial damage resulted from I/R occurs due oxidative stress evoked during the reperfusion phase. Here we demonstrate ischemia triggers specific redox reaction polyunsaturated fatty acids (PUFA)-phospholipids in cells, which acts as priming signaling initiates outbreak robust Using animal and vitro models, crucial lipid species were identified be oxidized PUFAs enriched phosphatidylethanolamines. multi-omics, arachidonic acid 15-lipoxygenase-1 (ALOX15) was primary mediator ischemia-provoked phospholipid peroxidation, further confirmed using chemogenetic approaches. Collectively, our results reveal ALOX15 induction phase “burning point” ignite oxidization into ferroptotic signals. This finding characterizes novel molecular mechanism for offers potential therapeutic target early intervention injury.

Language: Английский

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Mitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice

Cell Death Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: May 11, 2022

Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. The cyclic GMP-AMP synthase (cGAS)-stimulator interferon genes (STING) signaling pathway has been suggested to contribute the pathogenesis cardiovascular diseases. However, whether cGAS-STING involved in development DCM not established. Our study aimed determine role initiation nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome-induced pyroptosis and chronic inflammation during DCM. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via tail vein specifically knock down myocardial STING. After four weeks, myocardium-specific knockdown STING received injections streptozotocin (STZ; 50 mg/kg) high-fat diet induce diabetes. Measurements included echocardiography, immunohistochemical analyses, wheat germ agglutinin (WGA) staining, western blotting. Here, we showed was activated diabetic hearts, which indicated by increased phosphorylation TANK-binding kinase 1 (TBK1) (IFN) regulatory factor (IRF3), leading activation NLRP3 inflammasome hearts proinflammatory cytokine release into serum. Moreover, virus-9 mouse heart alleviated inflammatory response, prevented diabetes-induced hypertrophy, restored function. Mechanistically, palmitic acid (PA)-induced lipotoxicity impairs mitochondrial homeostasis, producing excessive reactive oxygen species (mtROS), results oxidative damage DNA (mtDNA) its cytoplasm while switching on cGAS-STING-mediated cardiomyocytes, thereby worsening progression cardiomyopathy. demonstrated caused mtDNA escape induced free fatty acids promoted responses cardiomyocytes inflammasome-dependent manner, thus promoting hypertrophy

Language: Английский

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Neuronal cell death mechanisms in Alzheimer’s disease: An insight

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Aug. 25, 2022

Regulated cell death (RCD) is an ordered and tightly orchestrated set of changes/signaling events in both gene expression protein activity responsible for normal development as well maintenance tissue homeostasis. Aberrant activation this pathway results by various mechanisms including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent death. Such pathological changes neurons alone or combination have been observed the pathogenesis neurodegenerative diseases Alzheimer’s disease (AD). Pathological hallmarks AD focus primarily on accumulation two main markers: amyloid β peptides abnormally phosphorylated tau proteins. These aggregates result formation A-β plaques neuro-fibrillary tangles (NFTs) induce neuroinflammation neurodegeneration over years to decades leading a multitude cognitive behavioral deficits. Autopsy findings reveal massive neuronal manifested form cortical volume shrinkage, reduction sizes gyri up 50% increase sulci. Multiple forms recorded from different studies conducted so far. However, understanding mechanism/s patients remains mystery trigger that aberrant RCD unknown because limited availability dying neurons. This review attempts elucidate process death, how it gets unregulated response intra extracellular stressors, their interplay role Disease human experimental models AD. Further we plan explore correlation amyloid-beta Tau with loss seen

Language: Английский

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Circulating tumor nucleic acids: biology, release mechanisms, and clinical relevance

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Jan. 21, 2023

Despite advances in early detection and therapies, cancer is still one of the most common causes death worldwide. Since each tumor unique, there a need to implement personalized care develop robust tools for monitoring treatment response assess drug efficacy prevent disease relapse.

Language: Английский

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Programmed cell death in atherosclerosis and vascular calcification

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(5)

Published: May 18, 2022

The concept of cell death has been expanded beyond apoptosis and necrosis to additional forms, including necroptosis, pyroptosis, autophagy, ferroptosis. These modalities play a critical role in all aspects life, which are noteworthy for their diverse roles diseases. Atherosclerosis (AS) vascular calcification (VC) major causes the high morbidity mortality cardiovascular disease. Despite considerable advances understanding signaling pathways associated with AS VC, exact molecular basis remains obscure. In article, we review mechanisms that mediate its implications VC. A better underlying VC may drive development promising therapeutic strategies.

Language: Английский

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