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Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 August 2024 | Viewed by 11431

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Special Issue Editor

Dr. Anne Vejux

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Guest Editor

Team “Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism”, Université de Bourgogne, 21000 Dijon, France
Interests: oxysterols; very-long-chain fatty acids; lipid metabolism; diet, peroxisomes; biotherapies; inflammation; cancer; cell cycle and apoptosis; autophagy; biological membranes; oxidative damage; biomarkers; neurodegenerative diseases
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issues, “Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 2.0”. Neurodegenerative diseases represent a major societal challenge. These are not diseases that have a short, life-threatening prognosis, they are instead very debilitating, inflict heavy demands on carers and require the establishment of appropriate centers for patient care. It is therefore essential that we understand more about the mechanisms involved in the physiopathogenesis of these diseases.

Neurodegenerative diseases include multiple demyelinating neurodegenerative diseases: multiple sclerosis and peroxisomal and nondemyelinating leukodystrophies, and Alzheimer’s disease, Parkinson’s disease, Niemann–Pick disease, Huntington’s disease, and amyotrophic lateral sclerosis or Charcot disease. Among the mechanisms involved in these pathologies, inflammation, oxidative stress, and cell death play crucial roles in their pathophysiology. It is therefore important to more thoroughly understand the involvement of cell death, inflammation, and oxidative stress in these diseases, as well as the cellular and molecular mechanisms that lead to it, and to identify the natural or unnatural molecules that can thwart these mechanisms. Apoptosis, autophagy, necroptosis, or other forms of cell death could be interesting therapeutic targets to aim at in order to combat the development of these neurodegenerative diseases. Cytokinic and non-cytokinic inflammation, as well as processes generating oxidative stress, could also be interesting targets in the pursuit of fighting these pathologies.

Dr. Anne Vejux
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

apoptosis
autophagy
necrosis
reticulum stress
natural molecules
oxidative stress
therapeutic
signalling pathways

Published Papers (7 papers)

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Research

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20 pages, 7867 KiB

Open AccessArticle

Positron Emission Tomography with [¹⁸F]ROStrace Reveals Progressive Elevations in Oxidative Stress in a Mouse Model of Alpha-Synucleinopathy

by Evan Gallagher, Catherine Hou, Yi Zhu, Chia-Ju Hsieh, Hsiaoju Lee, Shihong Li, Kuiying Xu, Patrick Henderson, Rea Chroneos, Malkah Sheldon, Shaipreeah Riley, Kelvin C. Luk, Robert H. Mach and Meagan J. McManus

Int. J. Mol. Sci. 2024, 25(9), 4943; https://doi.org/10.3390/ijms25094943 - 1 May 2024

Viewed by 701

Abstract

The synucleinopathies are a diverse group of neurodegenerative disorders characterized by the accumulation of aggregated alpha-synuclein (aSyn) in vulnerable populations of brain cells. Oxidative stress is both a cause and a consequence of aSyn aggregation in the synucleinopathies; however, noninvasive methods for detecting oxidative stress in living animals have proven elusive. In this study, we used the reactive oxygen species (ROS)-sensitive positron emission tomography (PET) radiotracer [¹⁸F]ROStrace to detect increases in oxidative stress in the widely-used A53T mouse model of synucleinopathy. A53T-specific elevations in [¹⁸F]ROStrace signal emerged at a relatively early age (6–8 months) and became more widespread within the brain over time, a pattern which paralleled the progressive development of aSyn pathology and oxidative damage in A53T brain tissue. Systemic administration of lipopolysaccharide (LPS) also caused rapid and long-lasting elevations in [¹⁸F]ROStrace signal in A53T mice, suggesting that chronic, aSyn-associated oxidative stress may render these animals more vulnerable to further inflammatory insult. Collectively, these results provide novel evidence that oxidative stress is an early and chronic process during the development of synucleinopathy and suggest that PET imaging with [¹⁸F]ROStrace holds promise as a means of detecting aSyn-associated oxidative stress noninvasively. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 3.0)

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26 pages, 35876 KiB

Open AccessArticle

The Construction and Validation of a Novel Ferroptosis-Related Gene Signature in Parkinson’s Disease

by Tingting Liu, Haojie Wu and Jianshe Wei

Int. J. Mol. Sci. 2023, 24(24), 17203; https://doi.org/10.3390/ijms242417203 - 6 Dec 2023

Viewed by 1523

Abstract

As a newly discovered regulated cell death mode, ferroptosis is associated with the development of Parkinson’s disease (PD) and has attracted much attention. Nonetheless, the relationship between ferroptosis and PD pathogenesis remains unclear. The GSE8397 dataset includes GPL96 and GPL97 platforms. The differential genes were analyzed by immune infiltration and Gene Set Enrichment Analysis (GSEA) (p < 0.05), and differential multiple |logFC| > 1 and weighted gene coexpression network analysis (WGCNA) were used to screen differential expression genes (DEGs). The intersection with 368 ferroptosis-related genes (FRGs) was conducted for gene ontology/Kyoto encyclopedia of gene and genome (GO/KEGG) enrichment analysis, gene expression analysis, correlation analysis, single-cell sequencing analysis, and prognosis analysis (area under the curve, AUC) and to predict relevant miRNAs and construct network diagrams using Cytoscape. The intersection genes of differentially expressed ferroptosis-related genes (DEFRGs) and mitochondrial dysfunction genes were validated in the substantia nigra of MPTP-induced PD mice models by Western blotting and immunohistochemistry, and the protein-binding pocket was predicted using the DoGSiteScorer database. According to the results, the estimated scores were positively correlated with the stromal scores or immune scores in the GPL96 and GPL97 platforms. In the GPL96 platform, the GSEA showed that differential genes were mainly involved in the GnRH signaling pathway, B cell receptor signaling pathway, inositol phosphate metabolism, etc. In the GPL97 platform, the GSEA showed that differential genes were mainly involved in the ubiquitin-mediated proteolysis, axon guidance, Wnt signaling pathway, MAPK signaling pathway, etc. We obtained 26 DEFRGs, including 12 up-regulated genes and 14 down-regulated genes, with good correlation. The area under the prognostic analysis curve (AUC > 0.700) showed a good prognostic ability. We found that they were enriched in different neuronal cells, oligodendrocytes, astrocytes, oligodendrocyte precursor cells, and microglial cells, and their expression scores were positively correlated, and selected genes with an AUC curve ≥0.9 were used to predict miRNA, including miR-214/761/3619-5p, miR-203, miR-204/204b/211, miR-128/128ab, miR-199ab-5p, etc. For the differentially expressed ferroptosis–mitochondrial dysfunction-related genes (DEF-MDRGs) (AR, ISCU, SNCA, and PDK4), in the substantia nigra of mice, compared with the Saline group, the expression of AR and ISCU was decreased (p < 0.05), and the expression of α-Syn and PDK4 was increased (p < 0.05) in the MPTP group. Therapeutic drugs that target SNCA include ABBV-0805, Prasinezumab, Cinpanemab, and Gardenin A. The results of this study suggest that cellular DEF-MDRGs might play an important role in PD. AR, ISCU, SNCA, and PDK4 have the potential to be specific biomarkers for the early diagnosis of PD. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 3.0)

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19 pages, 1866 KiB

Open AccessArticle

Repurposing Simvastatin in Parkinson’s Disease Model: Protection Is throughout Modulation of the Neuro-Inflammatory Response in the Substantia nigra

by Moisés Rubio-Osornio, Carmen T. Goméz-De León, Sergio Montes, Carmen Rubio, Camilo Ríos, Antonio Monroy and Jorge Morales-Montor

Int. J. Mol. Sci. 2023, 24(13), 10414; https://doi.org/10.3390/ijms241310414 - 21 Jun 2023

Viewed by 1370

Abstract

Parkinson’s disease is a neurodegenerative disorder characterized by oxidative stress and immune activation in the nigro-striatal pathway. Simvastatin regulates cholesterol metabolism and protects from atherosclerosis disease. Simvastatin-tween 80 was administered 7 days before sterotaxic intrastriatal administration of MPP⁺ (1-methyl-4-phenylpyridine) in rats. Fluorescent lipidic product formation, dopamine levels, and circling behavior were considered damage markers. Twenty-four hours and six days after, the animal group lesioned with MPP⁺ showed significant damage in relation to the control group. Animals pretreated with simvastatin significantly reduced the MPP⁺-induced damage compared to the MPP⁺ treated group. As apoptosis promotes neuroinflammation and neuronal degeneration in Parkinson’s disease, and since there is not currently a proteomic map of the nigro-striatum of rats and assuming a high homology among the identified proteins in other rat tissues, we based the search for rat protein homologs related to the establishment of inflammation response. We demonstrate that most proteins related to inflammation decreased in the simvastatin-treated rats. Furthermore, differential expression of antioxidant enzymes in striated tissue of rat brains was found in response to simvastatin. These results suggest that simvastatin could prevent striatal MPP⁺-induced damage and, for the first time, suggest that the molecular mechanisms involved in this have a protective effect. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 3.0)

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Review

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47 pages, 1356 KiB

Open AccessReview

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders

by Anna Stasiłowicz-Krzemień, Wiktoria Nogalska, Zofia Maszewska, Mateusz Maleszka, Maria Dobroń, Agnieszka Szary, Aleksandra Kępa, Marcin Żarowski, Katarzyna Hojan, Malgorzata Lukowicz and Judyta Cielecka-Piontek

Int. J. Mol. Sci. 2024, 25(11), 5749; https://doi.org/10.3390/ijms25115749 - 25 May 2024

Viewed by 258

Abstract

Neurological disorders present a wide range of symptoms and challenges in diagnosis and treatment. Cannabis sativa, with its diverse chemical composition, offers potential therapeutic benefits due to its anticonvulsive, analgesic, anti-inflammatory, and neuroprotective properties. Beyond cannabinoids, cannabis contains terpenes and polyphenols, which synergistically enhance its pharmacological effects. Various administration routes, including vaporization, oral ingestion, sublingual, and rectal, provide flexibility in treatment delivery. This review shows the therapeutic efficacy of cannabis in managing neurological disorders such as epilepsy, neurodegenerative diseases, neurodevelopmental disorders, psychiatric disorders, and painful pathologies. Drawing from surveys, patient studies, and clinical trials, it highlights the potential of cannabis in alleviating symptoms, slowing disease progression, and improving overall quality of life for patients. Understanding the diverse therapeutic mechanisms of cannabis can open up possibilities for using this plant for individual patient needs. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 3.0)

22 pages, 673 KiB

Open AccessReview

The Dual Role of Autophagy in Postischemic Brain Neurodegeneration of Alzheimer’s Disease Proteinopathy

by Ryszard Pluta

Int. J. Mol. Sci. 2023, 24(18), 13793; https://doi.org/10.3390/ijms241813793 - 7 Sep 2023

Cited by 2 | Viewed by 1358

Abstract

Autophagy is a self-defense and self-degrading intracellular system involved in the recycling and elimination of the payload of cytoplasmic redundant components, aggregated or misfolded proteins and intracellular pathogens to maintain cell homeostasis and physiological function. Autophagy is activated in response to metabolic stress or starvation to maintain homeostasis in cells by updating organelles and dysfunctional proteins. In neurodegenerative diseases, such as cerebral ischemia, autophagy is disturbed, e.g., as a result of the pathological accumulation of proteins associated with Alzheimer’s disease and their structural changes. Postischemic brain neurodegeneration, such as Alzheimer’s disease, is characterized by the accumulation of amyloid and tau protein. After cerebral ischemia, autophagy was found to be activated in neuronal, glial and vascular cells. Some studies have shown the protective properties of autophagy in postischemic brain, while other studies have shown completely opposite properties. Thus, autophagy is now presented as a double-edged sword with possible therapeutic potential in brain ischemia. The exact role and regulatory pathways of autophagy that are involved in cerebral ischemia have not been conclusively elucidated. This review aims to provide a comprehensive look at the advances in the study of autophagy behavior in neuronal, glial and vascular cells for ischemic brain injury. In addition, the importance of autophagy in neurodegeneration after cerebral ischemia has been highlighted. The review also presents the possibility of modulating the autophagy machinery through various compounds on the development of neurodegeneration after cerebral ischemia. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 3.0)

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13 pages, 770 KiB

Open AccessReview

Move Your Body toward Healthy Aging: Potential Neuroprotective Mechanisms of Irisin in Alzheimer’s Disease

by Tatiani Bellettini-Santos, Hemily Batista-Silva, Clairton Marcolongo-Pereira, Fernanda Cristina de Abreu Quintela-Castro, Rafael Mazioli Barcelos, Kelly Cristina Mota Braga Chiepe, Joamyr Victor Rossoni, Jr., Roberta Passamani-Ambrosio, Bruno Spalenza da Silva, Orlando Chiarelli-Neto and Michelle Lima Garcez

Int. J. Mol. Sci. 2023, 24(15), 12440; https://doi.org/10.3390/ijms241512440 - 4 Aug 2023

Viewed by 2299

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in older adults, having a significant global burden and increasing prevalence. Current treatments for AD only provide symptomatic relief and do not cure the disease. Physical activity has been extensively studied as a potential preventive measure against cognitive decline and AD. Recent research has identified a hormone called irisin, which is produced during exercise, that has shown promising effects on cognitive function. Irisin acts on the brain by promoting neuroprotection by enhancing the growth and survival of neurons. It also plays a role in metabolism, energy regulation, and glucose homeostasis. Furthermore, irisin has been found to modulate autophagy, which is a cellular process involved in the clearance of protein aggregates, which are a hallmark of AD. Additionally, irisin has been shown to protect against cell death, apoptosis, oxidative stress, and neuroinflammation, all of which are implicated in AD pathogenesis. However, further research is needed to fully understand the mechanisms and therapeutic potential of irisin in AD. Despite the current gaps in knowledge, irisin holds promise as a potential therapeutic target for slowing cognitive decline and improving quality of life in AD patients. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 3.0)

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18 pages, 551 KiB

Open AccessReview

Glymphatic System and Mitochondrial Dysfunction as Two Crucial Players in Pathophysiology of Neurodegenerative Disorders

by Kamila Kopeć, Stanisław Szleszkowski, Dariusz Koziorowski and Stanislaw Szlufik

Int. J. Mol. Sci. 2023, 24(12), 10366; https://doi.org/10.3390/ijms241210366 - 20 Jun 2023

Cited by 6 | Viewed by 2939

Abstract

Neurodegenerative diseases are a complex problem affecting millions of people around the world. The pathogenesis is not fully understood, but it is known that both insufficiency of the glymphatic system and mitochondrial disorders affect the development of pathology. It appears that these are not just two independent factors that coexist in the processes of neurodegeneration, but that they often interact and drive each other. Bioenergetics disturbances are potentially associated with the accumulation of protein aggregates and impaired glymphatic clearance. Furthermore, sleep disorders characteristic of neurodegeneration may impair the work of both the glymphatic system and the activity of mitochondria. Melatonin may be one of the elements linking sleep disorders with the function of these systems. Moreover, noteworthy in this context is the process of neuroinflammation inextricably linked to mitochondria and its impact not only on neurons, but also on glia cells involved in glymphatic clearance. This review only presents possible direct and indirect connections between the glymphatic system and mitochondria in the process of neurodegeneration. Clarifying the connection between these two areas in relation to neurodegeneration could lead to the development of new multidirectional therapies, which, due to the complexity of pathogenesis, seems to be worth considering. Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules 3.0)

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