Copper homeostasis and cuproptosis in health and disease

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

Published: Nov. 23, 2022

As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation intracellular can induce oxidative stress and perturbing cellular function, homeostasis tightly regulated. Recent studies identified novel copper-dependent form death called cuproptosis, which distinct from other known pathways underlying death. Cuproptosis occurs via binding to lipoylated enzymes tricarboxylic acid (TCA) cycle, leads subsequent protein aggregation, proteotoxic stress, ultimately Here, we summarize our current knowledge regarding metabolism, copper-related disease, characteristics mechanisms that regulate cuproptosis. In addition, discuss implications cuproptosis pathogenesis various disease conditions, including Wilson's neurodegenerative diseases, cancer, therapeutic potential targeting

Language: Английский

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Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

Medicinal Research Reviews, Journal Year: 2021, Volume and Issue: 42(1), P. 259 - 305

Published: May 6, 2021

Abstract Ischemic stroke caused by arterial occlusion is the most common type of stroke, which among frequent causes disability and death worldwide. Current treatment approaches involve achieving rapid reperfusion either pharmacologically or surgically, both are time‐sensitive; moreover, blood flow recanalization often ischemia/reperfusion injury. However, even though neuroprotective intervention urgently needed in event exact mechanisms neuronal during ischemic still unclear, consequently, capacity for drug development has remained limited. Multiple cell pathways implicated pathogenesis stroke. Here, we have reviewed these potential pathways, including intrinsic extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, pyroptosis. We also latest results pharmacological studies on summarized emerging targets with a focus clinical trials. These observations may help to further understand pathological events bridge gap between basic translational research reveal novel interventions.

Language: Английский

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Therapeutic Approach to Alzheimer’s Disease: Current Treatments and New Perspectives

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(6), P. 1117 - 1117

Published: May 24, 2022

Alzheimer’s disease (AD) is the most common cause of dementia. The pathophysiology this characterized by accumulation amyloid-β, leading to formation senile plaques, and intracellular presence neurofibrillary tangles based on hyperphosphorylated tau protein. In therapeutic approach AD, we can identify three important fronts: approved drugs currently available for treatment disease, which include aducanumab, donepezil, galantamine, rivastigmine, memantine, a combination memantine donepezil; therapies under investigation that work mainly Aβ pathology pathology, γ-secretase inhibitors, β-secretase α-secretase modulators, aggregation metal interfering drugs, enhance clearance, inhibitors protein hyperphosphorylation, promote clearance tau, finally, other alternative designed improve lifestyle, thus contributing prevention disease. Therefore, aim review was analyze describe current treatments possible future alternatives in AD.

Language: Английский

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Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis

Cellular and Molecular Immunology, Journal Year: 2022, Volume and Issue: 19(8), P. 913 - 924

Published: June 8, 2022

Language: Английский

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Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Aug. 19, 2022

Abstract Background Hypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression colorectal cancer (CRC), which dysregulation long non-coding RNAs (lncRNAs) is frequently observed. However, underlying mechanisms are not clearly defined. Methods The TCGA database was analyzed to identify differential lncRNA expression involved hypoxia-induced CRC progression. qRT-PCR conducted validate upregulation STEAP3-AS1 cell lines and tumor-bearing mouse zebrafish models under hypoxia. ChIP-qRT-PCR used detect transcriptional activation mediated by HIF-1α. RNA-seq, fluorescent situ hybridization, RNA pulldown, immunoprecipitation, co-immunoprecipitation, immunofluorescence immunoblot experiments were ascertain mechanisms. Functional assays performed both vitro vivo investigate regulatory /STEAP3/Wnt/β-catenin axis proliferation metastasis. Results Here, we identified antisense that highly expressed clinical tissues positively correlated with poor prognosis patients. Upregulation , induced HIF-1α-mediated activation, facilitated metastasis cells vivo. Mechanistically, interacted competitively YTH domain-containing family protein 2 (YTHDF2), N 6 -methyladenosine (m A) reader, leading disassociation YTHDF2 STEAP3 mRNA. This effect protected mRNA from m A-mediated degradation, enabling high subsequent production cellular ferrous iron (Fe 2+ ). Increased Fe levels elevated Ser 9 phosphorylation glycogen synthase kinase 3 beta (GSK3β) inhibited its activity, thus releasing β-catenin for nuclear translocation Wnt signaling support Conclusions Taken together, our study highlights facilitating involving axis, may provide novel diagnostic biomarkers or therapeutic targets benefit treatment. Graphical abstract Hypoxia-induced HIF-1α transcriptionally upregulates interacts YTHDF2, upregulating stability consequent expression. enhanced results ), induces inactivation GSK3β, contributing promote

Language: Английский

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Cerebral Iron Deposition in Neurodegeneration

Biomolecules, Journal Year: 2022, Volume and Issue: 12(5), P. 714 - 714

Published: May 17, 2022

Disruption of cerebral iron regulation appears to have a role in aging and the pathogenesis various neurodegenerative disorders. Possible unfavorable impacts accumulation include reactive oxygen species generation, induction ferroptosis, acceleration inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow examination macroscopic patterns brain deposits vivo, while modern analytical methods ex vivo enable determination metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes whole brain, cellular, subcellular diseases genetic sporadic origin. We provide an update on mechanisms, biomarkers, effects these disorders, focusing recent publications. In Parkinson’s disease, Friedreich’s several disorders neurodegeneration with group, there is focal siderosis, typically regions most pronounced neuropathological second group including multiple sclerosis, Alzheimer’s amyotrophic lateral sclerosis shows globus pallidus, caudate, putamen, cortical regions. Yet, other such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest diffuse deep gray matter pattern comparable even more extensive than that observed during normal aging. On microscopic level, are mostly dystrophic microglia variably accompanied by iron-laden macrophages astrocytes, implicating changes blood–brain barrier disturbance accumulation. Options potential benefits reducing strategies discussed. Future research investigating whether predispositions play Fe necessary. If confirmed, prevention further uptake individuals at risk may be key for preventing

Language: Английский

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Cuproptosis: Harnessing Transition Metal for Cancer Therapy

ACS Nano, Journal Year: 2023, Volume and Issue: 17(20), P. 19581 - 19599

Published: Oct. 11, 2023

Transition metal elements, such as copper, play diverse and pivotal roles in oncology. They act constituents of metalloenzymes involved cellular metabolism, function signaling molecules to regulate the proliferation metastasis tumors, are integral components metal-based anticancer drugs. Notably, recent research reveals that excessive copper can also modulate occurrence programmed cell death (PCD), known cuprotosis, cancer cells. This modulation occurs through disruption tumor metabolism induction proteotoxic stress. discovery uncovers a mode interaction between transition metals proteins, emphasizing intricate link homeostasis metabolism. Moreover, they provide innovative therapeutic strategies for precise diagnosis treatment malignant tumors. At crossroads chemistry oncology, we undertake comprehensive review elucidating molecular mechanisms underpinning cuproptosis. Additionally, summarize current nanotherapeutic approaches target cuproptosis an overview available laboratory clinical methods monitoring this process. In context emerging concepts, challenges, opportunities, emphasize significant potential nanotechnology advancement field.

Language: Английский

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Iron, ferroptosis, and ischemic stroke

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 165(4), P. 487 - 520

Published: March 13, 2023

Abstract Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism neuronal damage during stroke remains unclear; therefore, effective treatment post‐ischemic a critical challenge. Recently, iron has emerged as crucial factor in post‐reperfusion injuries, participating cell peroxidation, excitotoxicity, and distinctive death pathway, namely, ferroptosis. Since is tightly regulated brain important for functions, imbalance its metabolism, including overload deficiency, been shown to impact outcomes. This review summarizes current understanding pathological events associated with discusses relevant drug development. image

Language: Английский

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Mechanisms of ferroptosis in Alzheimer's disease and therapeutic effects of natural plant products: A review

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 164, P. 114312 - 114312

Published: May 19, 2023

Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by massive loss of specific neurons. It is a progressive disabling, severe and fatal complex disease. Due to its pathogenesis limitations clinical treatment strategies, it poses serious medical challenge burden worldwide. The AD not clear, potential biological mechanisms include aggregation soluble amyloid form insoluble plaques, abnormal phosphorylation tau protein formation intracellular neurofibrillary tangles (NFT), neuroinflammation, ferroptosis, oxidative stress metal ion disorders. Among them, ferroptosis newly discovered programmed cell death induced iron-dependent lipid peroxidation reactive oxygen species. Recent studies have shown that closely related AD, but the mechanism remains unclear. may be iron metabolism, amino acid metabolism affecting accumulation ions. Some chelating agents (deferoxamine, deferiprone), chloroiodohydroxyquine derivatives, antioxidants (vitamin E, lipoic acid, selenium), derivatives Fer-1, tet, etc. been in animal effective exert neuroprotective effects. This review summarizes regulation natural plant products on order provide reference information for future research development inhibitors.

Language: Английский

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Trace Elements in Alzheimer’s Disease and Dementia: The Current State of Knowledge

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(8), P. 2381 - 2381

Published: April 19, 2024

Changes in trace element concentrations are being wildly considered when it comes to neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. This study aims present the role that elements play central nervous system. Moreover, we reviewed mechanisms involved their neurotoxicity. Low zinc concentrations, well high levels of copper, manganese, iron, activate signalling pathways inflammatory, oxidative nitrosative stress response. Neurodegeneration occurs due association between metals proteins, which is then followed by aggregate formation, mitochondrial disorder, and, ultimately, cell death. In disease, low Zn suppress neurotoxicity induced β-amyloid through selective precipitation aggregation intermediates. High iron manganese cause intracellular α-synuclein, results synaptic dysfunction axonal transport disruption. caused accumulation Fe midbrain dopaminergic nucleus, pathogenesis multiple sclerosis derives from deficiency, leading an imbalance T functions. Aluminium disturbs homeostasis other a rise production oxygen reactive forms, leads cellular Selenium, with plays distinct process ferroptosis. Outlining influence have on oxidoreduction processes crucial recognising pathophysiology diseases may provide possible new methods for both avoidance therapy.

Language: Английский

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