Molecular mechanisms of ferroptosis and their involvement in brain diseases

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 244, P. 108373 - 108373

Published: March 8, 2023

Ferroptosis is a type of regulated cell death characterized by intracellular accumulation iron and reactive oxygen species, inhibition system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation lipid peroxidation. Since its discovery characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, involvement disease pathways. inducers include erastin, sorafenib, sulfasalazine glutamate, which, inhibiting prevent import cysteine into cells. RSL3, statins, Ml162 Ml210 induce ferroptosis peroxidase 4 (GPX4), which responsible for preventing formation peroxides, FIN56 withaferin trigger GPX4 degradation. On other side, inhibitors ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 BH4, interrupt peroxidation cascade. Additionally, deferoxamine, deferiprone N-acetylcysteine, targeting cellular pathways, also classified as inhibitors. Increased evidence has established distinct brain diseases, including Alzheimer's, Parkinson's Huntington's amyotrophic lateral sclerosis, multiple Friedreich's ataxia. Thus, deep understanding how contributes these it can be modulated, open new window opportunities novel therapeutic strategies targets. Other studies shown sensitivity cancer cells with mutated RAS induction that chemotherapeutic agents synergize tumor treatment. tempting consider may arise target mechanistic pathway treatment tumors. Therefore, this work provides an up-to-date review on molecular mechanisms their diseases. In addition, information main targets provided.

Language: Английский

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Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases

Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 214, P. 102270 - 102270

Published: April 18, 2022

Aggregation of specific proteins are histopathological hallmarks several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions ratiometric 3 repeat (3 R) 4 (4 isoforms progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) dystrophic neurites (LNs) Parkinson's (PD) dementia with (DLB). However, mixed brain protein pathologies have been frequently observed many these diseases normal aging brains, among which Aβ/tau tau/α-Syn crosstalks received increased attention. Interestingly, studies also shown synergistic interplay Aβ, tau, α-Syn suggesting a triumvirate. In this review, we summarize the emerging evidence aggregation pathophysiology, their overlap spectrum including AD, PSP, PiD, CBD, PD DLB. We discuss prognostic advancements made biomarker imaging techniques triumvirate proteinopathies. Finally, combined therapeutic modality involving biomarkers for future combinatorial immunotherapeutic targeting more than one aggregates. hope that multitarget approach will or additive effects to manage two might uncover promising strategy personalized combination therapies. Managing by optimizing diagnostic criteria correct immunotherapies be key factor success treatment.

Language: Английский

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Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress

Cells, Journal Year: 2022, Volume and Issue: 11(5), P. 851 - 851

Published: March 1, 2022

In response to environmental stimuli, cells make a series of adaptive changes combat the injury, repair damage, and increase tolerance stress. However, once damage is too serious repair, will undergo apoptosis protect overall through suicidal behavior. Upon external stimulation, some intracellular proteins turn into unfolded or misfolded protein, exposing their hydrophobic regions form protein aggregation, which may ultimately produce cells. Ubiquitin plays an important role in degradation these unnatural by tagging with ubiquitin chains ubiquitin-proteasome autophagy system. If two processes fail eliminate abnormal aggregates, move death. Dysregulation system (UPS) result development numerous diseases. This review focuses on molecular mechanisms UPS clearance relationship between dysregulation network

Language: Английский

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Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Sept. 20, 2022

Language: Английский

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Alpha Synuclein: Neurodegeneration and Inflammation

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5914 - 5914

Published: March 21, 2023

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in pathogenesis Parkinson’s disease and related disorders, synucleinopathies, but also several other neurodegenerative disorders with a more elusive role. This review analyzes activities α-Syn, different conformational states, monomeric, oligomeric fibrils, relation to neuronal dysfunction. The damage induced by α-Syn various conformers will be analyzed its capacity spread intracellular aggregation seeds prion-like mechanism. In view prominent role inflammation virtually all activity illustrated considering influence on glial reactivity. We others have described interaction between general cerebral dysfunctional α-Syn. Differences microglia astrocyte activation been observed when vivo presence oligomers has combined lasting peripheral inflammatory effect. reactivity was amplified, while astrocytes were damaged double stimulus, opening new perspectives for control synucleinopathies. Starting from our studies experimental models, we extended perspective find useful pointers orient future research potential therapeutic strategies disorders.

Language: Английский

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Associations Between Diabetes Mellitus and Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 542 - 542

Published: Jan. 10, 2025

Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years older type 2 diabetes (T2DM) cognitive impairment. It was found that is a major risk for decline, dementia, Parkinson's disease (PD), Alzheimer's (AD), Huntington's (HD), amyotrophic lateral sclerosis (ALS) other disorders. Different mechanisms of associations between these diseases have been suggested. For example, it postulated an impaired intracellular insulin signaling pathway, together with hyperglycemia hyperinsulinemia, may cause pathological changes, such as dysfunction the mitochondria, oxidative stress inflammatory responses, etc. association diseases, well associations, needs further investigation. aim this review to describe mellitus, especially 1 (T1DM) selected i.e., disease, sclerosis. Suggested also described.

Language: Английский

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Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

Biomolecules, Journal Year: 2021, Volume and Issue: 11(5), P. 767 - 767

Published: May 20, 2021

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause pathological mechanism in many NDs. Several studies have shown interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked Alzheimer’s disease (AD), α-synuclein, Parkinson’s (PD). To date, NDs constitute serious public health problem, causing financial burden for care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow progression these devastating disorders. Therefore, there an urgent need develop effective drugs incurable ailments. It expected targeting can serve therapeutic strategy since neurodegeneration. In this context, may offer great opportunities drug discovery review critically discusses role provides updated information on scientific evidence potentially be used fatal brain

Language: Английский

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Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(10)

Published: Sept. 17, 2021

Dopaminergic (DA) cell death in Parkinson's disease (PD) is associated with the gradual appearance of neuronal protein aggregates termed Lewy bodies (LBs) that are comprised vesicular membrane structures and dysmorphic organelles conjunction alpha-Synuclein (α-Syn). Although exact mechanism aggregate formation remains elusive, recent research suggests α-Syn-mediated alterations lysosomal degradation aggregated proteins - a process autophagy. Here, we used combination molecular biology immunochemistry to investigate effect α-Syn on autophagy turnover cultured human DA neurons post-mortem brain tissue. We found overexpression reduce by compromising fusion autophagosomes lysosomes, thus leading decrease autolysosomes. In accord compensatory increase plasma autophagosomes, enhanced number extracellular vesicles (EV) abundance autophagy-associated these EVs. Mechanistically, decreased v-SNARE SNAP29, member SNARE complex mediating autophagolysosome fusion. line, SNAP29 knockdown mimicked whereas co-expression reversed α-Syn-induced changes EV release ameliorated death. our results from neurons, stage-dependent reduction SNc tissue body pathology (LBP) cases. summary, demonstrate previously unknown intracellular and, as consequence, reduced autolysosome As such, findings will therefore support investigation pathological PD.

Language: Английский

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Therapeutic Insights on Ferroptosis in Parkinson's disease

European Journal of Pharmacology, Journal Year: 2022, Volume and Issue: 930, P. 175133 - 175133

Published: July 2, 2022

Language: Английский

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Integration of microfluidic channel on electrochemical-based nanobiosensors for monoplex and multiplex analyses: An overview

Journal of the Taiwan Institute of Chemical Engineers, Journal Year: 2023, Volume and Issue: 146, P. 104814 - 104814

Published: April 6, 2023

Language: Английский

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