Chiisanoside Mediates the Parkin/ZNF746/PGC-1α Axis by Downregulating MiR-181a to Improve Mitochondrial Biogenesis in 6-OHDA-Caused Neurotoxicity Models In Vitro and In Vivo: Suggestions for Prevention of Parkinson’s Disease

Antioxidants, Journal Year: 2023, Volume and Issue: 12(9), P. 1782 - 1782

Published: Sept. 20, 2023

The degeneration of dopamine (DA) neurons is known to be associated with defects in mitochondrial biogenesis caused by aging, environmental factors, or mutations genes, leading Parkinson's disease (PD). As PD has not yet been successfully cured, the strategy using small molecule drugs protect and restore a promising direction. This study evaluated efficacy synthetic chiisanoside (CSS) identified leaves Acanthopanax sessiliflorus prevent symptoms. results show that 6-hydroxydopamine (6-OHDA) model, CSS pretreatment can effectively alleviate reactive oxygen species generation apoptosis SH-SY5Y cells, thereby lessening C. elegans model including DA neuron degeneration, dopamine-mediated food sensitivity behavioral disorders, shortened lifespan. Mechanistically, we found could expression proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α), key biogenesis, its downstream related genes inhibited 6-OHDA. We further confirmed this due enhanced activity parkin ubiquitination degradation PGC-1α inhibitor protein Zinc finger 746 (ZNF746). Parkin siRNA treatment abolished effect CSS. Furthermore, 6-OHDA-induced miR-181a, which targets parkin. CSS's ability reverse reduction activation was after transfection anti-miR-181a miR-181a mimics. Therefore, neuroprotective mainly promotes regulating miR-181a/Parkin/ZNF746/PGC-1α axis. potentially opportunity developed into prevention agents.

Language: Английский

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A sporadic Parkinson’s disease model via silencing of the ubiquitin–proteasome/E3 ligase component, SKP1A

Journal of Neural Transmission, Journal Year: 2023, Volume and Issue: 131(6), P. 675 - 707

Published: Aug. 29, 2023

Abstract Our and other’s laboratory microarray-derived transcriptomic studies in human PD substantia nigra pars compacta (SNpc) samples have opened an avenue to concentrate on potential gene intersections or cross-talks along the dopaminergic (DAergic) neurodegenerative cascade sporadic (SPD). One emerging candidate identified was SKP1A (p19, S-phase kinase-associated protein 1A), found significantly decreased SNpc as confirmed later at level. SKP1 is part of Skp1, Cullin 1, F-box (SCF) complex, largest known class sophisticated ubiquitin–proteasome/E3-ligases directly interact with FBXO7 , a defective PARK15 -linked PD. This finding has led us hypothesis that targeted site-specific reduction Skp1 levels DAergic neuronal cell culture animal systems may result progressive loss neurons hopefully recreate motor disabilities animals. The second premise considers possibility both intrinsic extrinsic factors (e.g., manipulation selected genes mitochondria impairing toxins), alleged play central roles neurodegeneration PD, act concert modifiers deficiency-induced phenotype alterations (‘dual-hit’ neurodegeneration). To examine possible role phenotype, we initially knocked down expression embryonic mouse SN-derived line ( SN4741 ) short hairpin RNA (shRNA) lentiviruses (LVs). deficiency closely recapitulated cardinal features pathology such phenotypic markers cycle aberrations. Furthermore, cells displayed lethal when induced differentiate exhibiting proteinaceous round inclusion structures, which were almost identical composition Lewy bodies, hallmark These findings support for survival, differentiation. identification key player neuron function suggested mice terminal projections striatum. injected LV shRNA SN resulted within tyrosine hydroxylase immunoreactivity (TH-IR) striatum accompanied by time-dependent disabilities. vertical movements, rearing, be reminiscent early occurrence hypokinesia axial, postural instability According ‘dual-hit’ diseases, it predicted gene–gene and/or gene–environmental would sequentially propagate pathological process are compatible this conjecture showing genetic vulnerability caused knock renders especially sensitive Aldh1 exposure external stressors MPP + DA, been implicated pathology. Future consideration should given therapeutic window, via its induction genetically pharmacological, prevent degeneration striatal dopamine neurons, since UPS defective.

Language: Английский

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Mitochondrial Dysfunction and Its Role in Neurological Disorders

Published: Jan. 1, 2024

Mitochondria, pivotal cell organelles recognized for their paramount role in cellular energy production, play a crucial part neurological disorders such as Parkinson's disease (PD), Alzheimer's (AD), and multiple sclerosis when functionality falters. Among the repercussions of mitochondrial dysfunction, neuroinflammation emerges prominent concern, eliciting an upsurge generation reactive oxygen species (ROS). The deleterious effects these ROS on nerve cells induce cascade toward neurodegeneration. This chapter comprehensively delves into adverse implications dysfunction advancement diverse ailments, with particular emphasis neuroinflammation.

Language: Английский

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The Contribution of Mitochondrial Evolution and Dysfunction to Neurodegeneration

Oxford University Press eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 58 - 80

Published: July 1, 2024

Abstract Mitochondria carry their own circular DNA but heavily depend on the import of nucleus-encoded proteins. During human brain evolution, a rapid increase in size and neuronal complexity was accompanied by elevated energy requirements, possibly explaining why neurodegenerative disorders such as Parkinson’s disease (PD) Alzheimer’s well mental like schizophrenia—for which mitochondrial dysfunction is hallmark—are specific to humans. This chapter summarizes current understanding multifaceted involvement signaling normal aging neurological conditions with focus PD. Specifically, it concentrates possible phylogenetic components quality control, calcium dyshomeostasis, bioenergetics, maintenance mitochondria-mediated apoptosis inflammation. Finally, discusses challenges mitochondria-targeted therapy approaches that aim at preventing demise dopaminergic neurons PD patients.

Language: Английский

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Unravelling the protective effects of peptide isolated from marine sponge extract MS01 against SH-SY5Y cell line and its in-silico pharmacokinetic analysis

Human Gene, Journal Year: 2024, Volume and Issue: unknown, P. 201345 - 201345

Published: Oct. 1, 2024

Language: Английский

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Identification of biomarkers in Parkinson’s disease by comparative transcriptome analysis and WGCNA highlights the role of oligodendrocyte precursor cells

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: Nov. 20, 2024

Parkinson's disease (PD) is an age-related neurodegenerative characterized by the death of dopamine neurons in substantia nigra. A large number studies have focused on themselves, but so far, pathogenesis PD has not been fully elucidated.

Language: Английский

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Parkin R274W mutation affects muscle and mitochondrial physiology

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2024, Volume and Issue: 1870(7), P. 167302 - 167302

Published: June 13, 2024

Recessive mutations in the Parkin gene (PRKN) are most common cause of young-onset inherited parkinsonism. is a multifunctional E3 ubiquitin ligase that plays variety roles cell including degradation proteins and maintenance mitochondrial homeostasis, integrity, biogenesis. In 2001, R275W mutation PRKN was identified two unrelated families with multigenerational history postural tremor, dystonia Drosophila models showed selective progressive degeneration dopaminergic neuronal clusters, abnormalities, prominent climbing defects. Prkn mouse orthologue, amino acid R274 corresponds to human R275. Here we described an age-related motor impairment muscle phenotype R274W +/+ mice. vitro, correlates abnormal myoblast differentiation, defects, alteration mRNA protein levels. Our data suggest may impact physiology eventually proliferation differentiation.

Language: Английский

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COL8A2 Activation Enhances Function of Corneal Endothelial Cells through HIPPO Signaling/Mitochondria Pathway

Matrix Biology, Journal Year: 2024, Volume and Issue: 134, P. 119 - 131

Published: Oct. 11, 2024

Language: Английский

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Regulation of classical zinc fingers for neuronal signaling in the central nervous system

Bulletin of the Korean Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 29, 2024

Abstract Zinc finger (ZF) proteins are well‐known for their regulatory functions in the central dogma, and structural domains serve as promising scaffolds study of neurodegenerative diseases. These often contain multiple ZF domains, enabling interactions with target molecules that regulate transcription translation. The Cys 2 His (C H ) type found brain, associated long‐ short‐term memory, neuronal differentiation development, other physiological processes. classical C‐X ‐C‐X 12 ‐H‐X 3 ‐H have been detected studies Parkinson's disease (PD) closely linked to biological pathways involved a wide range In this review, we introduce three expressed brain: Parkin‐interacting substrate (PARIS), zinc BTB domain‐containing 20 (ZBTB20), protein 18 (ZNF18). We explore functional roles these brain. Each contains more than four well such KRAB, BTB, SCAN, which perform modular independently domains. Biophysical PARIS demonstrated its three‐ZF domain, PARIS(ZF2–4), forms hydrogen bonds insulin response sequences (IRSs) high specificity ( K d = 38.9 ± 2.4 nM). Metal coordination showed binds Co 2+ affinity 49.1 7.7 nM), strongly it also coordinates xenobiotic metal ions Fe Ni . Although Zn –PARIS(ZF2–4) specifically IRSs, –, 3+ – or cannot, due distortions domain structure disrupt bonding. brain‐specific exhibit common patterns, similar numbers sequence homology at C ‐terminus, whereas both N ‐terminal protein–protein interaction contribute versatility. Elucidating function offers avenues treatment diverse brain disorders, including Alzheimer's disease, PD, autism spectrum disorder.

Language: Английский

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Mechanism of baixiangdan capsules on anti-neuroinflammation: combining dry and wet experiments

Aging, Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 8, 2023

Neuroinflammation plays an important role in the pathogenesis of neurological disorders, and despite intensive research, treatment neuroinflammation remains limited. BaiXiangDan capsule (BXD) is widely used clinical practice. However, systematic studies on direct mechanisms BXD are still lacking. We systematically evaluated potential pharmacological using network analysis combined with experimental validation. Multiple databases to mine targets for bioactive ingredients, drug neuroinflammation. GO KEGG pathway was also performed. Interactions between active ingredients pivotal were confirmed by molecular docking. An model evaluate possible therapeutic BXD. Network revealed that Chrysoeriol, Kaempferol Luteolin exerted their anti-neuroinflammatory effects mainly acting such as NCOA2, PIK3CA PTGS2. Molecular docking results showed average affinity less than -5 kcal/mol, -8.286 kcal/mol. Pathways cancer found be a potentially pathway, involvement PI3K/AKT signaling pathways. In addition, vivo experiments ameliorated neural damage reduced neuronal cell death. Western blotting, RT-qPCR ELISA inhibited not only expression IL-1β, TNF-α NO, but NF-κB, MMP9 This study applied pharmacology explore against neuroinflammation, providing insight into

Language: Английский

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