Disorders of Endogenous and Exogenous Antioxidants in Neurological Diseases DOI Creative Commons
Izabela Korczowska-Łącka, Bartosz Słowikowski, Thomas Piekut

et al.

Antioxidants, Journal Year: 2023, Volume and Issue: 12(10), P. 1811 - 1811

Published: Sept. 29, 2023

In diseases of the central nervous system, such as Alzheimer's disease (AD), Parkinson's (PD), stroke, amyotrophic lateral sclerosis (ALS), Huntington's (HD), and even epilepsy migraine, oxidative stress load commonly surpasses endogenous antioxidative capacity. While processes have been robustly implicated in pathogenesis these diseases, significance particular antioxidants, both especially exogenous, maintaining redox homeostasis requires further research. Among enzymes catalase, superoxide dismutase, glutathione peroxidase are to disabling free radicals, thereby preventing damage cellular lipids, proteins, nucleic acids. Whether supplementation with endogenously occurring antioxidant compounds melatonin carries any benefit, however, remains equivocal. Similarly, while health benefits certain exogenous including ascorbic acid (vitamin C), carotenoids, polyphenols, sulforaphanes, anthocyanins touted, their clinical efficacy effectiveness neurological contexts need be more defined. Here, we review current literature on mechanisms mitigating comment possible benefit most common antioxidants AD, PD, ALS, HD, epilepsy, migraine. We selected a basically neurodegenerative nature.

Language: Английский

Mechanisms controlling cellular and systemic iron homeostasis DOI
Bruno Galy, Marcus Conrad, Martina U. Muckenthaler

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(2), P. 133 - 155

Published: Oct. 2, 2023

Language: Английский

Citations

296
GPX4 in cell death, autophagy, and disease DOI Creative Commons
Yangchun Xie, Rui Kang, Daniel J. Klionsky

et al.

Autophagy, Journal Year: 2023, Volume and Issue: 19(10), P. 2621 - 2638

Published: June 4, 2023

Selenoprotein GPX4 (glutathione peroxidase 4), originally known as PHGPX (phospholipid hydroperoxide glutathione peroxidase), is the main oxidoreductase in use of a reducing agent scavenging lipid peroxidation products. There are three isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct spatiotemporal expression patterns during embryonic development adult life. In addition to inducing phenotype ferroptosis, loss can some cells trigger apoptosis, necroptosis, pyroptosis, or parthanatos, which mediates accelerates developmental defects, tissue damage, sterile inflammation. The interaction autophagic degradation pathway further modulates cell fate response oxidative stress. Impaired function implicated tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, ischemia-reperfusion injury. Additionally, R152H mutation promote Sedaghatian-type spinal metaphyseal dysplasia, rare fatal disease newborns. Here, we discuss roles classical functions well emerging GPX4-regulated processes death, autophagy, disease.Abbreviations: AA: arachidonic acid; cGPX4: GPX4; CMA: chaperone-mediated autophagy; DAMPs: danger/damage-associated molecular patterns; mGPX4: nGPX4: GSDMD-N: N-terminal fragment GSDMD; I/R: ischemia-reperfusion; PLOOH: phospholipid hydroperoxide; PUFAs: polyunsaturated fatty acids; RCD: regulated death; ROS: reactive oxygen species; Se: selenium; SSMD: spondylometaphyseal dysplasia; UPS: ubiquitin-proteasome system

Language: Английский

Citations

230
Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion DOI Creative Commons
Qing‐zhang Tuo, Yu Liu, Zheng Xiang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 23, 2022

Abstract Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available remove clot, and mechanism of neuronal death during ischemic is still in debate. Ferroptosis increasingly appreciated as cell after ischemia various organs. Here we report that serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization subsequent esterification gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin ACSL4 genes/proteins, their pro-ferroptotic phosphatidylethanolamine lipid products, prominently altered upon middle cerebral artery occlusion rodents. Genetically or pharmacologically inhibiting multiple points this pathway attenuated outcomes models vitro vivo. Therefore, thrombin-ACSL4 axis may be key therapeutic target ameliorate injury stroke.

Language: Английский

Citations

195
The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities DOI Creative Commons

Kamari Weaver,

Rachid Skouta

Biomedicines, Journal Year: 2022, Volume and Issue: 10(4), P. 891 - 891

Published: April 13, 2022

The selenoprotein glutathione peroxidase 4 (GPX4) is one of the main antioxidant mediators in human body. Its central function involves reduction complex hydroperoxides into their respective alcohols often using reduced Glutathione (GSH) as a reducing agent. GPX4 has become hotspot therapeutic target biomedical research following its characterization chief regulator ferroptosis, and subsequent recognition specific pharmacological for treatment an extensive variety diseases including cancers neurodegenerative disorders. Several recent studies have provided insights how distinguished from rest family, unique biochemical properties GPX4, related to lipid peroxidation enzyme may be modulated potential target. This current report aims review literature underlying all these present up-to-date perspective on understanding

Language: Английский

Citations

130
Alzheimer’s disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs DOI Creative Commons
Ana Rita Monteiro, Daniel José Barbosa, Fernando Remião

et al.

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 211, P. 115522 - 115522

Published: March 28, 2023

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases that affect millions people worldwide, with both prevalence and incidence increasing age. It characterized by cognitive decline associated, specifically, degeneration cholinergic neurons. The problem this even more fundamental as available therapies remain fairly limited mainly focused on symptoms' relief. Although aetiology remains elusive, two main pathological hallmarks are described: i) presence neurofibrillary tangles formed unfolded protein aggregates (hyperphosphorylated Tau protein) ii) extracellular amyloid-beta peptide. Given complexity surrounding pathogenesis disease, several potential targets have been highlighted interrelated upon its progression, such oxidative stress accumulation metal ions. Thus, advances made development innovative multitarget therapeutical compounds to delay progression restore cell function. This review focuses ongoing research new insights emerging disease-modifying drugs for AD treatment. Furthermore, classical novel biomarkers early diagnosis their role in assisting improvement targeted will also be approached.

Language: Английский

Citations

121
Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis DOI Creative Commons
Baiyu Qiu, Fereshteh Zandkarimi,

Carla T. Bezjian

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1177 - 1190.e18

Published: Feb. 1, 2024

Language: Английский

Citations

108
Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis DOI Creative Commons
Michael S. Mortensen,

Jimena Ruiz,

Jennifer L. Watts

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 804 - 804

Published: March 4, 2023

Ferroptosis is a form of regulated cell death that intricately linked to cellular metabolism. In the forefront research on ferroptosis, peroxidation polyunsaturated fatty acids has emerged as key driver oxidative damage membranes leading death. Here, we review involvement (PUFAs), monounsaturated (MUFAs), lipid remodeling enzymes and in highlighting studies revealing how using multicellular model organism Caenorhabditis elegans contributes understanding roles specific lipids mediators ferroptosis.

Language: Английский

Citations

101
Cerebral Iron Deposition in Neurodegeneration DOI Creative Commons
Petr Dušek, Tim Hofer, Jan Alexander

et al.

Biomolecules, Journal Year: 2022, Volume and Issue: 12(5), P. 714 - 714

Published: May 17, 2022

Disruption of cerebral iron regulation appears to have a role in aging and the pathogenesis various neurodegenerative disorders. Possible unfavorable impacts accumulation include reactive oxygen species generation, induction ferroptosis, acceleration inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow examination macroscopic patterns brain deposits vivo, while modern analytical methods ex vivo enable determination metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes whole brain, cellular, subcellular diseases genetic sporadic origin. We provide an update on mechanisms, biomarkers, effects these disorders, focusing recent publications. In Parkinson’s disease, Friedreich’s several disorders neurodegeneration with group, there is focal siderosis, typically regions most pronounced neuropathological second group including multiple sclerosis, Alzheimer’s amyotrophic lateral sclerosis shows globus pallidus, caudate, putamen, cortical regions. Yet, other such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest diffuse deep gray matter pattern comparable even more extensive than that observed during normal aging. On microscopic level, are mostly dystrophic microglia variably accompanied by iron-laden macrophages astrocytes, implicating changes blood–brain barrier disturbance accumulation. Options potential benefits reducing strategies discussed. Future research investigating whether predispositions play Fe necessary. If confirmed, prevention further uptake individuals at risk may be key for preventing

Language: Английский

Citations

92
Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes DOI Creative Commons
Yumin Wang, Shuang Wu, Qiang Li

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(24)

Published: June 21, 2023

Emerging evidence suggests that ferroptosis, a unique regulated cell death modality is morphologically and mechanistically different from other forms of death, plays vital role in the pathophysiological process neurodegenerative diseases, strokes. Accumulating supports ferroptosis as critical factor diseases strokes, pharmacological inhibition therapeutic target for these diseases. In this review article, core mechanisms are overviewed roles strokes described. Finally, emerging findings treating through This demonstrates by bioactive small-molecule compounds (ferroptosis inhibitors) could be effective treatments highlights potential promising avenue used to prevent article will shed light on developing novel regimens slow down progression future.

Language: Английский

Citations

83
Iron overload‐induced ferroptosis of osteoblasts inhibits osteogenesis and promotes osteoporosis: An in vitro and in vivo study DOI
Zengxin Jiang, Hao Wang, Guobin Qi

et al.

IUBMB Life, Journal Year: 2022, Volume and Issue: 74(11), P. 1052 - 1069

Published: May 31, 2022

Abstract Growing evidence indicates that iron overload is an independent risk factor for osteoporosis. However, the mechanisms are not fully understood. The purpose of our study was to determine whether could lead ferroptosis in osteoblasts and explore involved overload‐induced osteoporosis vitro vivo. Ferric ammonium citrate used mimic conditions, while deferoxamine ferrostatin‐1 were inhibit MC3T3‐E1 cells vitro. ferroptosis, osteogenic differentiation mineralization assessed A mouse model established using dextran. Immunohistochemical analysis performed Enzyme‐linked immunosorbent assays calcein–alizarin red S labelling assess new bone formation. Dual x‐ray absorptiometry, micro‐computed tomography histopathological conducted evaluate results showed reduced cell viability, superoxide dismutase glutathione levels, increased reactive oxygen species generation, lipid peroxidation, malondialdehyde levels ferroptosis‐related protein expression, induced ultrastructural changes mitochondria. Iron also Inhibiting reversed described above. inhibited osteogenesis, promoted vivo, which be improved by ferrostatin‐1. These demonstrate plays a crucial role Maintaining homeostasis targeting might potential measures treating or preventing

Language: Английский

Citations

77