Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4753 - 4753

Published: April 26, 2024

Wilson disease is a genetic disorder of the liver characterized by excess accumulation copper, which found ubiquitously on earth and normally enters human body in small amounts via food chain. Many interesting details were published mechanistic steps, such as generation reactive oxygen species (ROS) cuproptosis causing copper dependent cell death. In patients with disease, also, increased iron deposits that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes subcellular organelles. All topics are covered this review article, addition diagnostic therapeutic issues disease. Excess Cu2+ primarily leads (ROS), evidenced early experimental studies exemplified detection hydroxyl radical formation using electron spin resonance (ESR) spin-trapping method. The ROS products follows principles Haber–Weiss reaction subsequent Fenton leading copper-related cuproptosis, thereby closely connected ROS. Copper due impaired biliary excretion caused inheritable malfunctioning or missing ATP7B protein. As result, disturbed cellular homeostasis prevails liver. Released from cells limited storage capacity, toxic circulation arrives at other organs, local injury. This explains why injures not only liver, but also brain, kidneys, eyes, heart, muscles, bones, explaining multifaceted clinical features Among these depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser–Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, arthralgia. addition, Coombs-negative hemolytic anemia key feature undetectable serum haptoglobin. modified Leipzig Scoring System helps diagnose Patients well-treated first-line chelators like D-penicillamine facilitate removal circulating bound albumin increase urinary excretion. Early chelation therapy improves prognosis. Liver transplantation an option viewed ultima ratio end-stage untreatable complications acute failure. finally thus be life-saving approach curative treatment replacing hepatic gene mutation. conclusion, representing molecular challenge.

Language: Английский

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Glial Perturbation in Metal Neurotoxicity: Implications for Brain Disorders

Neuroglia, Journal Year: 2025, Volume and Issue: 6(1), P. 4 - 4

Published: Jan. 6, 2025

Overexposure of humans to heavy metals and essential poses a significant risk for the development neurological neurodevelopmental disorders. The mechanisms through which these exert their effects include generation reactive oxygen species, mitochondrial dysfunction, activation inflammatory pathways, disruption cellular signaling. function glial cells in brain maintenance homeostasis cannot be overlooked. are particularly susceptible metal-induced neurotoxicity. Accumulation promotes microglial activation, triggering responses that can coincide with other neurotoxicity, inducing alteration synaptic transmission, cognitive deficit, neuronal damage. In this review, we highlighted role dysfunction some selected neurodegenerative diseases We further dive into how exposure such as nickel, manganese, methyl mercury, cadmium, iron, arsenic, lead affect functions microglia, astrocytes, oligodendrocytes they on relation Potential therapeutic interventions use new improved chelating agents antioxidant therapies might approach alleviating perturbations.

Language: Английский

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Perfluorooctane sulfonate mediates GSH degradation leading to oral keratinocytes ferroptosis and mucositis through activation of the ER stress-ATF4-CHAC1 axis

Ecotoxicology and Environmental Safety, Journal Year: 2025, Volume and Issue: 292, P. 117964 - 117964

Published: March 1, 2025

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant that induces inflammatory response and oxidative stress in oral mucosa. Ferroptosis, form of cell death characterized by iron-dependent lipid peroxidation (the degradation lipids), was believed to play crucial role pathogenesis mucositis; however, the involvement PFOS-induced ferroptosis remained unclear. Our findings demonstrated PFOS inhibited proliferation induced pro-apoptotic effects cells, with most pronounced observed human keratinocytes (HOK). significantly increased reactive oxygen species (ROS) peroxidation, depleted glutathione (GSH) HOK cells. Notably, decreased peroxidase 4 (GPX4) expression elevated Fe2 + levels, suggesting potential induction ferroptosis. Ferroptosis inhibitors mitigated GSH depletion, subsequently enhancing viability. Mechanistically, endoplasmic reticulum (ER) contributed nuclear translocation (from cytoplasm into nucleus) activating transcription factor (ATF4) up-regulated its downstream target gene Chac1. Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) catalyzed conversion cysteinylglycine 5-oxoproline, resulting depletion-a critical Knocking down CHAC1 attenuated Tauroursodeoxycholic acid (TUDCA), classical ER inhibitor, mucositis inhibiting ATF4/CHAC1 pathway activation. These elucidated toxicological mechanisms proposed therapeutic strategies counteract exposure mucositis.

Language: Английский

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Novel impact of metal ion-induced cell death on diabetic cardiomyopathy pathogenesis and therapy

APOPTOSIS, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Language: Английский

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Metal coordination polymer nanoparticles for cancer therapy

Essays in Biochemistry, Journal Year: 2025, Volume and Issue: 69(02)

Published: April 10, 2025

Metal ions are essential elements in biological processes and immune homeostasis. They can regulate cancer cell death through multiple distinct molecular pathways stimulate cells implicated antitumor responses, suggesting opportunities to design novel metal ion-based therapies. However, their small size high charge density result poor target uptake, uncontrolled biodistribution, rapid clearance from the body, reducing therapeutic efficacy increasing potential off-target toxicity. coordination polymer nanoparticles (MCP NPs) nanoscale networks composed of organic ligands linked via noncovalent interactions. MCP NPs offer a promising nanoplatform for reshaping into more drug-like formulations, improving vivo pharmacological performance index therapy applications. This review provides comprehensive overview inherent functions therapy, showcasing examples NP systems designed preclinical applications where drug delivery principles play critical role enhancing outcomes. versatile ion engineering approaches using selected ions, various ligands, functional payloads, enabling on-demand nano-drug designs that significantly improve reduce side effects effective therapy.

Language: Английский

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Metalloptosis: Metal Ions-Induced Programmed Cell Death Based on Nanomaterials for Cancer Therapy

MedMat., Journal Year: 2024, Volume and Issue: 1(1), P. 6 - 26

Published: June 19, 2024

Programmed cell death (PCD) is defined as regulated controlled by an intracellular program. While apoptosis was once thought to be the only kind of PCD, current understanding has expanded include other forms such pyroptosis, autophagy, and necroptosis. These processes, especially necroptosis, serve natural defenses that restrict cancer cells from surviving disseminating. However, have evolved various strategies evade including genetic mutations epigenetic modifications in key modulators PCD pathways. With continuous development nanotechnology, emerging nanomaterials (NMs) are considered break through this bottleneck due their intrinsic physicochemical properties. Especially, new kinds induced NMs, ferroptosis, cuproptosis, calcium overload, show gratifying potential therapy, which closely linked role metal ions. Additionally, ions-induced sodium zinc also emerged endless stream. Hence, we propose term “metalloptosis” describe ions summarize its application therapy NMs. This review will delve into critical design principles for engineering NMs involved metalloptosis provide a comprehensive summary ions-mediated therapies, focusing on nanoplatforms mechanisms action. We hope perspective based nanotechnology.

Language: Английский

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The roles of long non-coding RNAs in ovarian cancer: from functions to therapeutic implications

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

Published: April 25, 2024

Long non-coding RNAs (lncRNAs) are multifunctional and participate in a variety of biological processes gene regulatory networks. The deregulation lncRNAs has been extensively implicated diverse human diseases, especially cancers. Overwhelming evidence demonstrates that essential to the pathophysiological ovarian cancer (OC), acting as regulators involved metastasis, cell death, chemoresistance, tumor immunity. In this review, we illustrate expanded functions initiation progression OC elaborate on signaling pathways which they pitch. Additionally, potential clinical applications biomarkers diagnosis treatment were emphasized, cementing bridge communication between practice basic research.

Language: Английский

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The multifaceted perspectives on the regulation of lncRNAs in hepatocellular carcinoma ferroptosis: from bench-to-bedside

Clinical and Experimental Medicine, Journal Year: 2024, Volume and Issue: 24(1)

Published: July 3, 2024

Despite being characterized by high malignancy, morbidity, and low survival rates, the underlying mechanism of hepatocellular carcinoma (HCC) has not been fully elucidated. Ferroptosis, a non-apoptotic form regulated cell death, possesses distinct morphological, biochemical, genetic characteristics compared to other types death. Dysregulated actions within molecular network that regulates ferroptosis have identified as significant contributors progression HCC. Long non-coding RNAs (lncRNAs) emerged influential diverse cellular processes, regulating gene function expression through multiple mechanistic pathways. An increasing body evidence indicates deregulated lncRNAs are implicated in malignant events such proliferation, growth, invasion, metabolism influencing Therefore, elucidating inherent role modulatory functions on HCC might promote development novel therapeutic interventions for this disease. This review provides succinct overview roles ferroptosis-related treatment, aiming drive promising targets biomarkers patients.

Language: Английский

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Unveiling Cuproptosis: Mechanistic insights, roles, and leading advances in oncology

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: unknown, P. 189180 - 189180

Published: Sept. 1, 2024

Language: Английский

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Metallomic analysis of urine from individuals with and without Covid-19 infection reveals extensive alterations in metal homeostasis

Journal of Trace Elements in Medicine and Biology, Journal Year: 2024, Volume and Issue: 86, P. 127557 - 127557

Published: Oct. 30, 2024

Language: Английский

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