Copper Metabolism and Cuproptosis: Molecular Mechanisms and Therapeutic Perspectives in Neurodegenerative Diseases

Current Medical Science, Journal Year: 2024, Volume and Issue: 44(1), P. 28 - 50

Published: Feb. 1, 2024

Abstract Copper is an essential trace element, and plays a vital role in numerous physiological processes within the human body. During normal metabolism, body maintains copper homeostasis. deficiency or excess can adversely affect cellular function. Therefore, homeostasis stringently regulated. Recent studies suggest that trigger specific form of cell death, namely, cuproptosis, which triggered by excessive levels intracellular copper. Cuproptosis induces aggregation mitochondrial lipoylated proteins, loss iron-sulfur cluster proteins. In neurodegenerative diseases, pathogenesis progression neurological disorders are linked to This review summarizes advances cuproptosis nervous system diseases. offers research perspectives provide new insights into targeted treatment diseases based on cuproptosis.

Language: Английский

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PANoptosis signaling enables broad immune response in psoriasis: From pathogenesis to new therapeutic strategies

Computational and Structural Biotechnology Journal, Journal Year: 2023, Volume and Issue: 23, P. 64 - 76

Published: Nov. 28, 2023

Language: Английский

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WTAP participates in neuronal damage by protein translation of NLRP3 in an m6A-YTHDF1-dependent manner after traumatic brain injury

International Journal of Surgery, Journal Year: 2024, Volume and Issue: 110(9), P. 5396 - 5408

Published: June 14, 2024

Background Traumatic brain injury (TBI) is a common complication of acute and severe neurosurgery. Remodeling N6-methyladenosine (m6A) stabilization may be an attractive treatment option for neurological dysfunction after TBI. In the present study, authors explored epigenetic methylation RNA-mediated NLRP3 inflammasome activation Methods Neurological dysfunction, histopathology, associated molecules were examined in conditional knockout (CKO) WTAP [flox/flox, Camk2a-cre] , flox/flox pAAV-U6-shRNA-YTHDF1-transfected mice. Primary neurons used vitro to further explore molecular mechanisms action WTAP/YTHDF1 following neural damage. Results The found that m6A levels upregulated at early stage TBI, deletion did not affect function but promoted functional recovery Conditional suppressed neuroinflammation TBI phase: could directly act on mRNA, regulate mRNA level, promote expression neuronal injury. Further investigation YTH domain YTHDF1 bind protein expression. mutation or silencing improved injury, inhibited Caspase-1 activation, decreased IL-1β levels. This effect was mediated via suppression translation, which also reversed stimulative overexpression inflammation. Conclusions Our results indicate participates damage by translation m6A-YTHDF1-dependent manner WTAP/m6A/YTHDF1 downregulation therapeutics viable promising approach preserving can provide support targeted drug development.

Language: Английский

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VDAC1, as a downstream molecule of MLKL, participates in OGD/R-induced necroptosis by inducing mitochondrial damage

Heliyon, Journal Year: 2023, Volume and Issue: 10(1), P. e23426 - e23426

Published: Dec. 11, 2023

Ischemia-reperfusion (I/R) injury constitutes a significant risk factor for range of diseases, including ischemic stroke, myocardial infarction, and trauma. Following the restoration blood flow post-tissue ischemia, oxidative stress can lead to various forms cell death, necrosis, apoptosis, autophagy, necroptosis. Recent evidence has highlighted crucial role mitochondrial dysfunction in I/R injury. Nevertheless, there remains much be explored regarding molecular signaling network governing death under conditions stress. Voltage-dependent anion channel 1 (VDAC1), major component outer membrane, is closely involved regulation death. In cellular model oxygen-glucose deprivation reoxygenation (OGD/R), which effectively simulates vitro, our study reveals that OGD/R induces VDAC1 oligomerization, consequently exacerbating Furthermore, we have revealed translocation mixed lineage kinase domain-like protein (MLKL) mitochondria, where it interacts with following injury, leading an increased membrane permeability. Notably, inhibition MLKL by necrosulfonamide hinders binding VDAC1, primarily affecting MLKL, reduces OGD/R-induced oligomerization. Collectively, findings provide preliminary functional association between

Language: Английский

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Akkermansia muciniphila-Nlrp3 is involved in the neuroprotection of phosphoglycerate mutase 5 deficiency in traumatic brain injury mice

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 23, 2023

Introduction Gut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following brain injury (TBI). Phosphoglycerate mutase 5 (PGAM5), mitochondrial serine/threonine protein phosphatase, resides in membrane and regulates homeostasis metabolism. Mitochondria mediates intestinal barrier gut microbiome. Objectives This study investigated association between PGAM5 microbiota mice with TBI. Methods The controlled cortical impact was established genetically-ablated Pgam5 ( −/− ) or wild type, WT male were treated fecal transplantation (FMT) from Akkermansia muciniphila A. ). Then abundance, blood metabolites, neurological function, nerve detected. Results Treated antibiotics for suppressing partially relieved role deficiency improvement initial inflammatory factors motor dysfunction post-TBI. knockout exhibited an increased abundance mice. FMT enabled better maintenance amino acid metabolism peripherial environment than that TBI-vehicle mice, which suppressed neuroinflammation improved deficits, negatively associated mucosal Moreover, ameliorated by regulating Nlrp3 inflammasome activation cerebral cortex Conclusion Thus, present provides evidence involved microbiota-mediated injury, -Nlrp3 contributing peripheral effects.

Language: Английский

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Regulated Cell Death of Retinal Ganglion Cells in Glaucoma: Molecular Insights and Therapeutic Potentials

Cellular and Molecular Neurobiology, Journal Year: 2023, Volume and Issue: 43(7), P. 3161 - 3178

Published: June 20, 2023

Language: Английский

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Mechanisms and Therapeutic Strategies for NLRP3 Degradation via Post-Translational Modifications in Ubiquitin-proteasome and Autophagy Lysosomal Pathway

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117476 - 117476

Published: March 4, 2025

Language: Английский

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FOXO3-induced microRNA-128-3p promotes the progression of spinal cord injury in mice via regulating NLRP3 inflammasome-mediated pyroptosis

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 21, 2025

Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate and complex pathophysiologic mechanisms. Pyroptosis, inflammatory form of cell death triggered by certain inflammasomes, has key role in variety diseases, including SCI. However, it is unclear whether microRNAs (miRNAs), novel regulators the SCI, are involved SCI-induced pyroptosis. Two GEO miRNA expression profiles (GSE158195 GSE90452) were downloaded, differentially expressed miRNAs analyzed bioinformatics methods. An vivo animal model vitro cellular SCI constructed female C57BL/6 mice BV-2 cells for studying possible roles FOXO3, miR-128-3p NLRP3-mediated pyroptosis Markers ROS, inflammation measured RT-qPCR, Western blotting, immunofluorescence, flow cytometry, enzyme-linked immunosorbent assays. Histopathological changes spinal tissue detected using hematoxylin eosin immunohistochemical. The Basso-Beattie-Bresnahan (BBB) score was used to evaluate motor function each group. Bioinformatics analysis GSE158195 GSE90452 datasets revealed significant downregulation miR-128-3p, phenomenon that consistently observed model. Functionally, upregulation improved functional behavioral recovery, relieved pathological injury, repressed oxidative stress, alleviated mouse models. We also confirmed Thioredoxin-interacting protein (TXNIP) target gene overexpression TXNIP can effectively reverse improvement Moreover, we found transcription factor FOXO3 facilitated expression, its resulted similar effects To best our knowledge, this first report demonstrating secondary through modulation pathway. Our results suggest FOXO3/miR-128-3p/TXNIP/NLRP3-mediated axis may be potential therapeutic

Language: Английский

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Astragaloside IV Improves Muscle Atrophy by Modulating the Activity of UPS and ALP via Suppressing Oxidative Stress and Inflammation in Denervated Mice

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Language: Английский

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OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

Cell Biochemistry and Function, Journal Year: 2023, Volume and Issue: 41(8), P. 1162 - 1173

Published: Sept. 10, 2023

This study investigated the role of phospholipase D (PLD) in retinal ischemia-reperfusion (I/R) injury using an oxygen-glucose deprivation/reperfusion (OGD/R) model commonly used I/R research. To create vitro cellular model, pharmacological inhibitors and small interfering RNA (siRNA) were to target PLD1 PLD2 pigment epithelial (RPE) cells. Treatment with PLD siRNA reduced reactive oxygen species (ROS) malondialdehyde (MDA) induced by OGD/R RPE cells increased levels superoxide dismutase (SOD) glutathione (GSH), indicating a reduction oxidative damage improvement antioxidant system. Next, we showed that inhibiting or intracellular iron lipid peroxidation, which are critical factors ferroptosis. Additionally, modulated expression proteins involved regulation ferroptosis, including GPX4, SLC7A11, FTH1, ACSL4. We also roles preventing pyroptosis, another form programmed cell death associated inflammation. Our found significantly production pro-inflammatory cytokines activated caspase-1, NLRP3, ASC, cleaved-caspase 1 (C-caspase-1), GSDMD-N cells, pyroptosis induction. However, inhibition knockdown inhibited activation NLRP3 inflammasome, Taken together, our findings support hypothesis signaling pathway plays key OGD/R-induced ferroptosis induction may be potential therapeutic for treating dysfunction degeneration.

Language: Английский

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