Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson’s Disease with Potential Therapeutic Implications

Biomolecules, Journal Year: 2025, Volume and Issue: 15(1), P. 149 - 149

Published: Jan. 19, 2025

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder marked by the progressive degeneration of midbrain dopaminergic neurons and resultant locomotor dysfunction. Despite over two centuries recognition as chronic disease, exact pathogenesis PD remains elusive. The onset progression involve multiple complex pathological processes, with dysfunctional autophagy elevated oxidative stress serving critical contributors. Notably, emerging research has underscored interplay between in pathogenesis. Given limited efficacy therapies targeting either dysfunction or stress, it crucial to elucidate intricate mechanisms governing their develop more effective therapeutics. This review overviews role nuclear factor erythroid 2-related 2 (Nrf2), pivotal transcriptional regulator orchestrating cellular defense against these processes. By elucidating key processes PD, this will deepen our comprehensive understanding multifaceted underlying may uncover potential strategies for its prevention treatment.

Language: Английский

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Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors

Neuroscience Bulletin, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Language: Английский

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Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications

Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 12(10), P. 3743 - 3782

Published: June 11, 2022

UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and homologous protein of autophagy related (Atg) yeast UNC-51 Caenorhabditis elegans. ULK1 well-known for activation, which evolutionarily conserved transport indispensable to maintain cell homeostasis. As the direct target energy nutrition-sensing may contribute distribution utilization cellular resources response metabolism closely associated with multiple pathophysiological processes. Moreover, has been widely reported play crucial role human diseases, including cancer, neurodegenerative cardiovascular disease, infections, subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, non-autophagy function emerging, indicating that non-autophagy-relevant signaling network linked diseases under some specific contexts. Therefore, this review, we summarized structure functions initiator, focus on new approaches, further elucidated key roles non-autophagy. Additionally, discussed relationships between well illustrated rapid progress better understanding discovery more candidate drugs targeting ULK1, will provide clue novel ULK1-targeted therapeutics future.

Language: Английский

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Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(17), P. 11454 - 11477

Published: Aug. 25, 2022

Neurodegenerative diseases (NDs) are currently incurable that cause progressive degeneration of nerve cells. Many the disease-causing proteins NDs "undruggable" for traditional small-molecule inhibitors (SMIs). None compounds attenuated amyloid-β (Aβ) accumulation process have entered clinical practice, and many phase III trials SMIs Alzheimer's disease (AD) failed. In recent years, emerging targeted protein degradation (TPD) technologies such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimaeras (LYTACs), autophagy-targeting (AUTACs) with TPD-assistive click-formed (CLIPTACs) deubiquitinase-targeting chimera (DUBTAC) developed rapidly. vitro in vivo experiments also confirmed TPD technology can target ND pathogenic proteins, bringing hope treatment NDs. Herein, we review latest technologies, introduce their targets technical characteristics, discuss potential research, providing a new perspective development field.

Language: Английский

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Fasting: From Physiology to Pathology

Advanced Science, Journal Year: 2023, Volume and Issue: 10(9)

Published: Feb. 3, 2023

Overnutrition is a risk factor for various human diseases, including neurodegenerative metabolic disorders, and cancers. Therefore, targeting overnutrition represents simple but attractive strategy the treatment of these increasing public health threats. Fasting as dietary intervention combating has been extensively studied. practiced millennia, only recently have its roles in molecular clock, gut microbiome, tissue homeostasis function emerged. can slow aging most species protect against These centuried unfading adventures explorations suggest that fasting potential to delay help prevent treat diseases while minimizing side effects caused by chronic interventions. In this review, recent animal studies concerning role underlying mechanism physiology pathology are summarized, therapeutic highlighted, combination pharmacological discussed new regimen diseases.

Language: Английский

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Cellular Compartmentalization, Glutathione Transport and Its Relevance in Some Pathologies

Antioxidants, Journal Year: 2023, Volume and Issue: 12(4), P. 834 - 834

Published: March 29, 2023

Reduced glutathione (GSH) is the most abundant non-protein endogenous thiol. It a ubiquitous molecule produced in organs, but its synthesis predominantly liver, tissue charge of storing and distributing it. GSH involved detoxification free radicals, peroxides xenobiotics (drugs, pollutants, carcinogens, etc.), protects biological membranes from lipid peroxidation, an important regulator cell homeostasis, since it participates signaling redox, regulation degradation proteins (S-glutathionylation), signal transduction, various apoptotic processes, gene expression, proliferation, DNA RNA synthesis, etc. transport vital step cellular homeostasis supported by liver through providing extrahepatic organs (such as kidney, lung, intestine, brain, among others) with said antioxidant. The wide range functions within which shows that glutathione’s role goes beyond being simple antioxidant agent; therefore, importance this tripeptide needs to be reassessed broader metabolic perspective.

Language: Английский

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Autophagy in Parkinson’s Disease

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1435 - 1435

Published: Sept. 22, 2023

Parkinson’s disease (PD) is a devastating associated with accumulation of α-synuclein (α-Syn) within dopaminergic neurons, leading to neuronal death. PD characterized by both motor and non-motor clinical symptoms. Several studies indicate that autophagy, an important intracellular degradation pathway, may be involved in different neurodegenerative diseases including PD. The autophagic process mediates the protein aggregates, damaged unneeded proteins, organelles, allowing their clearance, thereby maintaining cell homeostasis. Impaired autophagy cause abnormal proteins. Incomplete or impaired explain neurotoxic aggregates several Indeed, have suggested contribution α-Syn accumulation, death neuroinflammation. In this review, we summarize recent literature on involvement pathogenesis.

Language: Английский

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Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(7), P. 2815 - 2853

Published: April 24, 2024

Regulated cell death (RCD) is a controlled form of orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, modulating immunity. Accumulating evidence has recently revealed that evasion frequently the primary cause tumor survival. Several have garnered attention promising cancer therapies due their ability induce regression prevent relapse, comparable apoptosis. Moreover, they offer potential solutions for overcoming acquired resistance tumors toward drugs. With an increasing understanding underlying mechanisms governing these subroutines, growing number small-molecule compounds targeting single multiple pathways been discovered, providing novel strategies current therapy. In this review, we comprehensively summarized regulatory emerging mainly including autophagy-dependent death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic NETotic lysosome-dependent immunogenic (ICD). Furthermore, focused on discussing related compounds. brief, insightful findings may provide valuable guidance investigating individual collaborative approaches towards different ultimately driving discovery target significantly enhance future therapeutics.

Language: Английский

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Physiological functions of ULK1/2

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(15), P. 168472 - 168472

Published: Feb. 2, 2024

UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine that best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing nutrient status of a cell, ULK1/2 integrate signals from upstream cellular energy sensors such as mTOR AMPK relay them to downstream components machinery. also play indispensable roles selective pathway, removing damaged mitochondria, invading pathogens, toxic protein aggregates. Additional functions have emerged beyond autophagy, including trafficking, RNP granule dynamics, signaling events impacting innate immunity, axon guidance, homeostasis, cell fate. Therefore, it is no surprise alterations expression activity been linked with pathophysiological processes, cancer, neurological disorders, cardiovascular diseases. Growing evidence suggests function biological rheostats, tuning intra extra-cellular cues. Given broad physiological relevance, candidate targets small molecule activators or inhibitors may pave way development therapeutics treatment diseases humans.

Language: Английский

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Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson’s disease

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Sept. 12, 2024

Language: Английский

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