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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Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 7, 2025

Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption homeostatic regulation, and abnormalities in dynamics. The escaped activates cytosolic sensors, especially cyclic gmp-amp synthase (cGAS) signalling inflammasome, initiating neuroinflammatory cascades via pathways, exacerbating spectrum neurological pathologies. therapeutic promise targeting discussed detail, underscoring necessity for multifaceted strategy that encompasses preservation homeostasis, prevention leakage, reestablishment dynamics, inhibition activation sensors. Advancing our understanding complex interplay between neuroinflammation imperative developing precision interventions disorders.

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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The necroptosis-related lncRNA ENSG00000253385.1 promotes the progression of esophageal squamous cell carcinoma by targeting the miR-16-2-3p/VDAC1 axis

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 21, 2025

Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive malignancies. Our previous studies revealed necroptosis-related lncRNA ENSG00000253385.1 was an independent prognostic factor for ESCC. However, specific regulatory mechanisms are unknown. This study aimed to investigate expression in ESCC tissues and its relationship with clinicopathological features patient prognosis, explore potential mechanism cells. We detected location cells by fluorescence situ hybridization (FISH). FISH quantitative real-time polymerase chain reaction (qRT‒PCR) were used detect gene Cell proliferation, migration apoptosis evaluated CCK-8 assay, wound healing, transwell migration, invasion flow cytometry assay. The levels protein western blot. binding sites between miR-16-2-3p or voltage-dependent anion channel 1 (VDAC1) predicted bioinformatics database confirmed dual luciferase reporter Results that higher than adjacent tissues. High expression, positive lymph node metastasis clinical stage III associated poor overall survival (OS) patients ESCC, risk factors prognosis located cytoplasm. MiR-16-2-3p had a direct targeting relation ship VDAC1. inhibitor promoted invasion, inhibited Knockdown could inhibit promote apoptosis, result increases proteins p-receptor-interacting kinase 3 (RIPK3)/RIPK3 p-mixed lineaae domain-like (MLKL)/MLKL decrease VDAC1 cells, whereas inhibition rescued these effects. Therefore, ENSG00000253385.1/ miR-16-2-3p/VDAC1 axis may be considered as predictive biomarker target

Language: Английский

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Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 29, 2025

Abstract Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One the greatest barriers to developing treatments for IRDs is heterogeneity these disorders, with causative mutations identified in over 280 genes. It therefore priority find therapies applicable broad range genetic causes. To do so requires greater understanding common or overlapping molecular pathways that lead photoreceptor death and processes through which they converge. Here, we characterise contribution different cell mechanisms degeneration loss throughout disease progression humanised mouse models IRDs. Using single-cell transcriptomics, identify transcriptional signatures degenerating photoreceptors. Further, show genetically functionally distinct IRD models, early defects autophagy mitochondrial damage exist, triggering by necroptosis later stages. These results suggest that, regardless underlying cause, likely contribute insights provide potential therapeutic targets novel, gene-agnostic majority patients.

Language: Английский

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TAK1 at the crossroads of multiple regulated cell death pathways: from molecular mechanisms to human diseases

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

Published: March 6, 2025

Regulated cell death (RCD), the form of that can be genetically controlled by multiple signaling pathways, plays an important role in organogenesis, tissue remodeling, and maintenance organism homeostasis is closely associated with various human diseases. Transforming growth factor-beta-activated kinase 1 (TAK1) a member serine/threonine protein family, which respond to different internal external stimuli participate inflammatory immune responses. Emerging evidence suggests TAK1 regulator at crossroad RCD including apoptosis, necroptosis, pyroptosis, PANoptosis. The regulation affects disease progression through therapeutic strategies targeting have been proposed for diseases, central nervous system cancers. In this review, we provide overview downstream pathways regulated its binding proteins. Their critical regulatory roles forms are also summarized. addition, discuss potential treatment specific focus on neurological disorders cancer.

Language: Английский

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Plantamajoside: A potentially novel botanical agent for diabetes mellitus management

World Journal of Diabetes, Journal Year: 2025, Volume and Issue: 16(5)

Published: April 24, 2025

Diabetes mellitus (DM) and its associated complications are metabolic disorders characterized by hyperglycemia, leading to high morbidity reduced quality of life worldwide. This global healthcare problem imposes substantial personal social burdens that warrant comprehensive in-depth investigation. Plantamajoside (PMS), a naturally bioactive ingredient derived from the traditional Chinese medicinal herb Plantaginis Herba , exhibits range pharmacological properties, including anti-inflammatory, antioxidative, antitumor effects, has been traditionally utilized in clinical applications such as removing phlegm clearing heat. However, potential biological impact PMS on DM remains largely unexplored. Recent research Wang et al reported therapeutic type 2 (T2DM) elucidated underlying molecular mechanisms. Specifically, mitigates endoplasmic reticulum stress apoptosis pancreatic β-cells upregulating DnaJ heat shock protein family (Hsp40) member C1, thereby alleviating β-cell damage ameliorating T2DM progression. Given novel protective effect β-cells, this natural emerges an innovative promising strategy for improving outcomes. shown modulate key signaling pathways involved multiple types regulated cell death (RCD), autophagy. Various forms RCD, apoptosis, ferroptosis, pyroptosis, autophagy, PANoptosis, contribute pathogenesis complications. There is significant exert effects against these RCD provide multitarget approach therapy. Therefore, further exploration into whether shields coupled with elucidating mechanisms, will facilitate development more effective strategies DM. Additionally, investigation conjunction other approaches warranted enhance efficacy

Language: Английский

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VDAC in Retinal Health and Disease

Biomolecules, Journal Year: 2024, Volume and Issue: 14(6), P. 654 - 654

Published: June 4, 2024

The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further processed before they sent to brain be interpreted images. retina unique in that continuously exposed has highest metabolic rate demand energy amongst all tissues body. Consequently, very susceptible oxidative stress. VDAC, pore outer membrane mitochondria, shuttles metabolites between mitochondria cytosol normally protects cells from damage, but when cell’s integrity greatly compromised initiates cell death. There three isoforms existing evidence indicates expressed retina. However, their precise localization function each type unknown. It appears most retinal express substantial amounts VDAC2 VDAC3, presumably protect them Photoreceptors VDAC2, HK2, PKM2—key proteins Warburg pathway also these cells. Consistent with role initiating death, VDAC overexpressed degenerative diseases retinitis pigmentosa, age related macular degeneration (AMD), glaucoma. Treatment antioxidants or inhibiting oligomerization reduced expression improved survival. Thus, may promising therapeutic candidate treatment diseases.

Language: Английский

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Integration of Theory and Practice in Medical Morphology Curriculum in Postgraduate Training: A Flipped Classroom and Case-based Learning Exercise

Current Medical Science, Journal Year: 2023, Volume and Issue: 43(4), P. 741 - 748

Published: July 17, 2023

Language: Английский

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Bioinformatics analysis and verification of m6A related genes based on the construction of keloid diagnostic model

International Wound Journal, Journal Year: 2023, Volume and Issue: 20(7), P. 2700 - 2717

Published: March 10, 2023

Abstract Keloids are formed due to abnormal hyperplasia of the skin connective tissue. We explored relationship between N6‐methyladenosine (m6A)‐related genes and keloids. The transcriptomic datasets (GSE44270 GSE185309) keloid normal tissues samples were obtained from Gene Expression Omnibus database. constructed m6A landscape verified corresponding using immunohistochemistry. extracted hub for unsupervised clustering analysis protein–protein interaction (PPI) network; gene ontology enrichment was performed determine biological processes or functions affected by differentially expressed (DEGs). immune infiltration keloids microenvironment single‐sample set CIBERSORT. Differential expression several observed two groups; insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3 ) significantly upregulated in patients. PPI elucidated six with significant differences sample groups. Enrichment revealed that DEGs mainly enriched cell division, proliferation, metabolism. Moreover, immunity‐related pathways observed. Therefore, results this study will provide a reference elucidation pathogenesis therapeutic targets

Language: Английский

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