Relationship between enriched environment and neurodegeneration: a review from mechanism to therapy

Clinical Epigenetics, Год журнала: 2025, Номер 17(1)

Опубликована: Янв. 24, 2025

Enriched environment (EE), as a non-pharmacological intervention, has garnered considerable attention for its potential to ameliorate neurodegenerative diseases (NDs). This review delineated the impact of EE on biological functions associated with NDs, emphasizing role in enhancing neural plasticity, reducing inflammation, and bolstering cognitive performance. We discussed molecular underpinnings effects EE, including modulation key signaling pathways such extracellular regulated kinase 1/2 (ERK1/2), mitogen-activated protein kinases (MAPK), AMPK/SIRT1, which were implicated neuroprotection synaptic plasticity. Additionally, we scrutinized influence epigenetic modifications autophagy, processes pivotal ND pathogenesis. Animal models, encompassing both rodents larger animals, offer insights into disease-modifying underscoring complementary approach pharmacological interventions. In summary, emerges promising strategy augment function decelerate progression NDs.

Язык: Английский

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N7-methylguanosine modification in cancers: from mechanisms to therapeutic potential

Journal of Hematology & Oncology, Год журнала: 2025, Номер 18(1)

Опубликована: Янв. 29, 2025

N7-methylguanosine (m7G) is an important RNA modification involved in epigenetic regulation that commonly observed both prokaryotic and eukaryotic organisms. Their influence on the synthesis processing of messenger RNA, ribosomal transfer allows m7G modifications to affect diverse cellular, physiological, pathological processes. are pivotal human diseases, particularly cancer progression. On one hand, modification-associated modulate tumour progression malignant biological characteristics, including sustained proliferation signalling, resistance cell death, activation invasion metastasis, reprogramming energy metabolism, genome instability, immune evasion. This suggests they may be novel therapeutic targets for treatment. other aberrant expression molecules linked clinicopathological staging, lymph node unfavourable prognoses patients with cancer, indicating their potential as biomarkers. review consolidates discovery, identification, detection methodologies, functional roles modification, analysing mechanisms by which contribute development, exploring clinical applications diagnostics therapy, thereby providing innovative strategies identification targeted

Язык: Английский

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Multi-omics analyses reveal that Sirtuin 5 promotes the development of pre-recruitment follicles by inhibiting the autophagy-lysosome pathway in chicken granulosa cells

Poultry Science, Год журнала: 2025, Номер 104(3), С. 104884 - 104884

Опубликована: Фев. 7, 2025

The development of pre-recruitment follicles plays a critical role in determining egg-laying performance poultry. This study combines proteomic and metabolomic analyses to explore changes proteins metabolites, elucidate key regulatory mechanism involved chicken follicular development. Histological examination revealed significant increase yolk deposition small yellow (SYF) compared white (SWF). Metabolomics analysis identified significantly enriched differential metabolites (DMs) between SWF SYF pathways such as Lysosome, Ferroptosis, Biosynthesis unsaturated fatty acids, Tryptophan metabolism. Particularly, Adenosine-5'-Diphosphate (ADP) was downregulated during recruitment the lysosome pathway. Proteomic that differentially expressed (DEPs) were including Glutathione metabolism, Cholesterol Arginine proline amino acid biosynthesis. Among these DEPs, NAD-dependent protein deacetylase sirtuin 5 (SIRT5) upregulated, while lysosomal-associated membrane 1 (LAMP1) down-regulated follicles. SIRT5 linked negative regulation reactive oxygen species whereas LAMP1 associated with autophagy pathways. Further validation experiments demonstrated high expression SYF, particularly granulosa cells (GCs). Silencing GCs resulted increased ROS production upregulated autophagy-related LC3Ⅱ Beclin1, well markers LAMP1. Conversely, lipid droplet p62 suppressed. inhibited. Taken together, findings suggest upregulation promotes by inhibiting autophagy-lysosome pathway GCs.

Язык: Английский

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Pathobiology of the autophagy-lysosomal pathway in the Huntington’s disease brain

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 30, 2024

Abstract Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis Huntington’s disease (HD). Although lowering mHTT by stimulating autophagy has been a possible therapeutic strategy, role competence autophagy-lysosomal pathway (ALP) during HD progression in human remains largely unknown. Here, we used multiplex confocal ultrastructural immunocytochemical analyses ALP functional markers relation aggresome pathology striatum less affected cortex brains staged from HD2 HD4 Vonsattel neuropathological criteria compared controls. Immunolabeling revealed localization HTT/mHTT vesicular compartments labeled autophagy-related adaptor proteins p62/SQSTM1 ubiquitin, cathepsin D (CTSD) as well HTT-positive inclusions. comparatively normal at HD2, neurons later stages exhibited progressive enlargement clustering CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently than cortex. These changes were accompanied rises p62/SQSTM1, particularly their fragments, but not cortex, increases LAMP1 LAMP2 RNA protein. Importantly, no blockage autophagosome formation autophagosome-lysosome fusion was detected, thus pinpointing substrate clearance deficits basis for flux declines. The findings collectively suggest that upregulated lysosomal biogenesis preserved proteolysis maintain early-stage HD, failure advanced contributes HTT build-up potential neurotoxicity. support prospect stimulation applied early stages, when machinery is fully competent, may have benefits patients.

Язык: Английский

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Autophagy–lysosomal-associated neuronal death in neurodegenerative disease

Acta Neuropathologica, Год журнала: 2024, Номер 148(1)

Опубликована: Сен. 11, 2024

Язык: Английский

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Trehalose Ameliorates Zebrafish Emotional and Social Deficits Caused by CLN8 Dysfunction

Cells, Год журнала: 2025, Номер 14(1), С. 55 - 55

Опубликована: Янв. 5, 2025

CLN8 and other neuronal ceroid lipofuscinoses (NCLs) often lead to cognitive decline, emotional disturbances, social deficits, worsening with disease progression. Disrupted lysosomal pH, impaired autophagy, defective dendritic arborization contribute these symptoms. Using a cln8−/− zebrafish model, we identified significant impairments in locomotion, anxiety, aggression, along subtle deficits interactions, positioning as useful model for therapeutic studies NCL. Our findings show that trehalose, an autophagy enhancer, ameliorates modestly improves behavior predator avoidance mutant zebrafish. This finding aligns animal models clinical reports suggestive of behavioral improvements NCL patients. Trehalose holds promise agent CLN8, warranting further research into its neuroprotective mechanisms applications.

Язык: Английский

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Aberrant expression of long noncoding RNAs regulates inflammasome activation via oxidative stress: A novel mechanism for neuroinflammation and neurodegeneration in Parkinson's disease

Clinical and Experimental Neuroimmunology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

Abstract Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, leading to hallmark motor symptoms such as bradykinesia, tremors, and rigidity. Emerging evidence suggests that dysregulation or aberrant expression long noncoding RNAs (lncRNAs) plays critical role pathogenesis PD activating inflammasome, either directly via oxidative stress. Aberrant lncRNA has been linked alterations genes related stress, causing an imbalance between reactive oxygen species (ROS) antioxidant defenses. This contributes mitochondrial dysfunction neuronal damage. The NLRP3 inflammasome multiprotein complex comprising sensor protein (eg, NLRP3), adaptor (ASC), effector (caspase‐1). Its activation involves priming NF‐κB signaling triggered ROS, dysfunction, death‐associated molecular patterns, extracellular ATP. Once activated, promotes cleavage maturation proinflammatory cytokines IL‐1β IL‐18, amplifying neuroinflammation neurodegeneration PD. Crosstalk dysregulated lncRNAs, ROS production, creates vicious cycle neurodegeneration, exacerbating progression. review explores mechanisms linking PD, through It also highlights key lncRNAs involved these processes. Furthermore, potential therapeutic strategies targeting pathways, antioxidants, modulators, inhibitors, offer promising avenues mitigate slow

Язык: Английский

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Lysosome Functions in Atherosclerosis: A Potential Therapeutic Target

Cells, Год журнала: 2025, Номер 14(3), С. 183 - 183

Опубликована: Янв. 24, 2025

Lysosomes in mammalian cells are recognized as key digestive organelles, containing a variety of hydrolytic enzymes that enable the processing both endogenous and exogenous substrates. These organelles digest various macromolecules recycle them through autophagy–lysosomal system. Recent research has expanded our understanding lysosomes, identifying not only centers degradation but also crucial regulators nutrient sensing, immunity, secretion, other vital cellular functions. The lysosomal pathway plays significant role vascular regulation is implicated diseases such atherosclerosis. During atherosclerotic plaque formation, macrophages initially engulf large quantities lipoproteins, triggering pathogenic responses include dysfunction, foam cell subsequent atherosclerosis development. Lysosomal along with inefficient apoptotic accumulation modified low-density negatively impacts lesion progression. studies have highlighted dysfunction contributes critically to cell- stage-specific manner. In this review, we discuss mechanisms biogenesis its regulatory lesions. Based on these functions, propose targeting lysosomes could offer novel therapeutic approach for atherosclerosis, shedding light connection between disease progression while offering new insights into potential anti-atherosclerotic strategies.

Язык: Английский

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Neuronal endolysosomal acidification relies on interactions between transmembrane protein 184B (TMEM184B) and the vesicular proton pump

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 2, 2025

Abstract Disruption of endolysosomal acidification is a hallmark several neurodevelopmental and neurodegenerative disorders. Impaired causes accumulation toxic protein aggregates disrupts neuronal homeostasis, yet the molecular mechanisms regulating pH in neurons remain poorly understood. A critical regulator lumenal vacuolar ATPase (V-ATPase), proton pump whose activity depends on dynamic assembly its V0 V1 subdomains. In this study, we identify transmembrane 184B (TMEM184B) as novel neurons. TMEM184B an evolutionarily conserved 7-pass required for synaptic structure function, sequence variation disorders, but mechanism effect unknown. We performed proteomic analysis TMEM184B-interacting proteins identified enrichment components involved endosomal trafficking including V-ATPase. localizes to early late endosomes, further supporting role system. Loss results significant reductions within cultured mouse cortical This alteration associated with impaired V-ATPase subcomplexes mutant brain, suggesting by which promotes flux through pathway. Overall, these findings new contributor maintaining function provide mechanistic basis disrupted human TMEM184B-associated nervous system Significance Statement Endolysosomal essential regulation remains Here, key process, establishing first known cellular role. show that interacts (V-ATPase) subdomains, facilitating acidification. neurons, potentially impairing proteostasis. These reveal maintenance insight into link neurological work advances our understanding suggests could improve outcomes diseases involving lysosomal dysfunction.

Язык: Английский

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Microenvironment-Specific Enrichment Strategy Enables Lysosomal Proteomic Dynamics Analysis

Analytical Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 3, 2025

Lysosomes are vital organelles for degradation, recycling, and cellular homeostasis, impacting signaling metabolism. Analyzing the lysosomal proteome dynamics is key to understanding these roles, but acidic environment low abundance of lysosomes make proteomic analysis challenging. Herein, we developed a lysosome-localizable reactive diazirine molecule MDA demonstrated its enhanced labeling capability in microenvironment. Furthermore, introduced novel microenvironment-specific enrichment (MiSE) strategy profiling proteome, combining MDA-based with affinity enrichment. We successfully applied MiSE profile living SH-SY5Y cells, achieving coverage 132 lysosome-annotated proteins. Moreover, by coupling data-independent acquisition (DIA) analysis, explored dynamic changes upon inhibition ubiquitin-proteasome system using four proteasome inhibitors. Our results reveal 117 UPS-inhibition-related proteins, highlighting their involvement stress response cell cycle regulation. Notably, observe distinct signatures each inhibitor, suggesting unique mechanisms UPS inhibition. Therefore, offers powerful tool investigating providing insights into homeostasis disease pathogenesis. This approach holds significant potential advancing function developing therapeutic strategies.

Язык: Английский

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