A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease

Chemical Science, Journal Year: 2023, Volume and Issue: 14(35), P. 9427 - 9438

Published: Jan. 1, 2023

Ferroptosis, an iron-dependent cell death, plays a crucial role in the pathology of Alzheimer's disease (AD). Several characteristics AD, including excessive iron accumulation, elevated lipid peroxide and reactive oxygen species (ROS) levels, decreased glutathione peroxidase 4 (GPX4) align with features ferroptosis. While traditional methods inhibiting ferroptosis have centered on chelating Fe trapping radicals, therapeutic strategies that modulate GPX4 axis to mitigate AD are yet be explored. This report introduces naturally occurring polyphenols (PPs) as dual-acting agents synergistically alleviate AD. The mechanisms action encompass modulation amyloid tau cascade, reduction oxidative stress, mitochondrial rescue, inhibition For first time, we show single multifunctional molecule, tannic acid (TA) binds at activator site GPX4, augmenting both its activity cellular providing conceptually innovative integrated approach for treating via GPX4-ferroptosis axis. ability TA enhance levels under conditions opens up newer promising avenues combating crosstalk between

Language: Английский

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Fecal Microbiota Transplantation Reduces Pathology and Improves Cognition in a Mouse Model of Alzheimer’s Disease

Cells, Journal Year: 2022, Volume and Issue: 12(1), P. 119 - 119

Published: Dec. 28, 2022

Characterized by the presence of amyloid plaques, neurofibrillary tangles and neuroinflammation, Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no known treatment or cure. Global projections warrant an urgent rapid therapeutic for this devastating disease. Fecal microbiota transplantation (FMT) widely accepted safely used recurrent Clostridium difficile infection other metabolic diseases such as diabetes mellitus. FMT has also been demonstrated to be possible AD therapeutic. We examined potential in robust, mouse model report that brief, 7-day regimen 'plaque-busting' behavior-modifying effects treated 5xFAD mice. Importantly, we show donor age plays important role efficacy these findings further investigation human trials.

Language: Английский

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Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer’s Disease: Experimental and Computational Insights

ACS Omega, Journal Year: 2023, Volume and Issue: 8(5), P. 4508 - 4526

Published: Jan. 25, 2023

Alzheimer's disease (AD) is the most common form of dementia, affecting millions people around world. Even though causes AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks development have been related high concentration metal cations. These roles include participation these cations in production reactive oxygen species, which involved neuronal damage. In order avoid increment oxidative stress, multifunctional ligands used coordinate proposed as a possible treatment AD. this review, we present recent advances experimental and computational works aiming understand role two redox active essential transition-metal (Cu Fe) one nonbiological (Al) proposals on stop or revert damaging effects promoted by

Language: Английский

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G-quadruplexes and associated proteins in aging and Alzheimer’s disease

Frontiers in Aging, Journal Year: 2023, Volume and Issue: 4

Published: June 1, 2023

Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer’s disease (AD). characterized by progressive cognitive decline, memory loss, and neuropsychiatric behavioral symptoms, accounting most of the reported dementia cases. This now becoming major challenge burden on modern society, especially with aging population. Over last few decades, significant understanding pathophysiology AD has been gained studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, neuroinflammation. review focuses role non-canonical secondary structures DNA/RNA G-quadruplexes (G4s, G4-DNA, G4-RNA), G4-binding proteins (G4BPs), helicases, their roles in AD. Being critically important cellular function, G4s are involved regulation DNA RNA processes, replication, transcription, translation, localization, degradation. Recent studies have also highlighted G4-DNA’s inducing double-strand breaks that cause genomic instability G4-RNA’s participation regulating stress granule formation. emphasizes significance processes how homeostatic imbalance may contribute to

Language: Английский

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Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease

Redox Biology, Journal Year: 2024, Volume and Issue: 71, P. 103119 - 103119

Published: March 11, 2024

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the build-up of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Ferroptosis, an iron (Fe)-dependent form cell death plays significant role in multifaceted AD pathogenesis through generation reactive oxygen species (ROS), mitochondrial damage, lipid peroxidation, reduction glutathione peroxidase 4 (GPX4) enzyme activity levels. Aberrant liquid-liquid phase separation (LLPS) tau drives growth maturation NFTs contributing to pathogenesis. In this study, we strategically combined structural functional properties gallic acid (GA) cyclic dipeptides (CDPs) synthesize hybrid molecules that effectively target both ferroptosis toxicity AD. This innovative approach marks paradigm shift from conventional therapeutic strategies. first report synthetic small molecule (GCTR) combats ferroptosis, simultaneously restoring enzymatic enhancing cellular levels its master regulator, GPX4. Further, GCTR disrupts Fe3+-induced LLPS tau, aids attenuation abnormal fibrillization. The synergistic action combating toxicity, bolstered GPX4 enhancement modulation LLPS, holds promise for development molecule-based novel therapeutics

Language: Английский

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Mechanistic insights and emerging therapeutic stratagems for Alzheimer’s disease

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 97, P. 102309 - 102309

Published: April 13, 2024

Language: Английский

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Polycatechols inhibit ferroptosis and modulate tau liquid–liquid phase separation to mitigate Alzheimer's disease

Materials Horizons, Journal Year: 2024, Volume and Issue: 11(13), P. 3082 - 3089

Published: Jan. 1, 2024

Polycatechols modulate amyloid-associated toxicities, arrest labile iron, inhibit lipid peroxidation, and regulate tau liquid–liquid phase separation (LLPS) to mitigate the pathological nexus between ferroptosis AD.

Language: Английский

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Pathogenesis of Alzheimer’s Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential

ACS Chemical Neuroscience, Journal Year: 2023, Volume and Issue: 14(18), P. 3291 - 3317

Published: Sept. 8, 2023

Alzheimer's disease is a most prevalent form of dementia all around the globe and currently poses significant challenge to healthcare system. Currently available drugs only slow progression this rather than provide proper containment. Identification multiple targets responsible for in last three decades established it as multifactorial neurodegenerative disorder that needs novel multifunctional agents its management possible reason failure single target clinical drugs. 1,2,3-Triazole miraculous nucleus medicinal chemistry first choice development hybrid molecules. Apart from that, an integral component various trials well practice. This review focused on pathogenesis 1,2,3-triazole containing derivatives developed recent potential anti-Alzheimer's agents. The will (A) precise insight including cholinergic, amyloid, tau, monoamine oxidases, glutamate, calcium, reactive oxygen species hypothesis (B) design hypothesis, structure–activity relationships, pharmacological outcomes baseline research groups working drug designing potent, safer, effective candidates future.

Language: Английский

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Targeting misfolding and aggregation of the amyloid-β peptide and mutant p53 protein using multifunctional molecules

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(11), P. 1372 - 1388

Published: Jan. 1, 2024

We highlight recent advances in the development of multifunctional molecules designed to limit misfolding and aggregation intrinsically disordered biomolecules, with a focus on amyloid-beta peptide AD mutant p53 protein cancer.

Language: Английский

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Nanomodulators That Target Alzheimer’s Disease: A Review

ACS Applied Nano Materials, Journal Year: 2024, Volume and Issue: 7(4), P. 3515 - 3545

Published: Feb. 7, 2024

The vastness and multidimensional adversity of Alzheimer's disease (AD) impede the outgrowth its therapeutic research. Needless to say, application nanoscience has amplified progress prophylaxis therapeutics development for AD. In this Review, we will elaborate on advancement a nanoparticle-based alternative targeting AD in terms design, approach, mechanism action, limitations associated with their clinical availability. So far, blood–brain barrier (BBB) is one major hurdles drugs any neurodegenerative disease. Here, focus current state-of-the-art crossing BBB.

Language: Английский

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