Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases
Open accessAbstract
The Mediterranean diet is associated with health benefits due to bioactive compounds such as polyphenols. The biological activities of three polyphenols (quercetin (QCT), resveratrol (RSV), apigenin (API)) were evaluated in mouse neuronal N2a cells in the presence of 7-ketocholesterol (7KC), a major cholesterol oxidation product increased in patients with age-related diseases, including neurodegenerative disorders. In N2a cells, 7KC (50 µM; 48 h) induces cytotoxic effects characterized by an induction of cell death. When associated with RSV, QCT and API (3.125; 6.25 µM), 7KC-induced toxicity was reduced. The ability of QCT, RSV and API to prevent 7KC-induced oxidative stress was characterized by a decrease in reactive oxygen species (ROS) production in whole cells and at the mitochondrial level; by an attenuation of the increase in the level and activity of catalase; by attenuating the decrease in the expression, level and activity of glutathione peroxidase 1 (GPx1); by normalizing the expression, level and activity of superoxide dismutases 1 and 2 (SOD1, SOD2); and by reducing the decrease in the expression of nuclear erythroid 2-like factor 2 (Nrf2) which regulates antioxidant genes. QCT, RSV and API also prevented mitochondrial dysfunction in 7KC-treated cells by counteracting the loss of mitochondrial membrane potential (ΨΔm) and attenuating the decreased gene expression and/or protein level of AMP-activated protein kinase α (AMPKα), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) implicated in mitochondrial biogenesis. At the peroxisomal level, QCT, RSV and API prevented the impact of 7KC by counteracting the decrease in ATP binding cassette subfamily D member (ABCD)3 (a peroxisomal mass marker) at the protein and mRNA levels, as well as the decreased expresssion of genes associated with peroxisomal biogenesis (Pex13, Pex14) and peroxisomal β-oxidation (Abcd1, Acox1, Mfp2, Thiolase A). The 7KC-induced decrease in ABCD1 and multifunctional enzyme type 2 (MFP2), two proteins involved in peroxisomal β-oxidation, was also attenuated by RSV, QCT and API. 7KC-induced cell death, which has characteristics of apoptosis (cells with fragmented and/or condensed nuclei; cleaved caspase-3; Poly(ADP-ribose) polymerase (PARP) fragmentation) and autophagy (cells with monodansyl cadaverine positive vacuoles; activation of microtubule associated protein 1 light chain 3–I (LC3-I) to LC3-II, was also strongly attenuated by RSV, QCT and API. Thus, in N2a cells, 7KC induces a mode of cell death by oxiapoptophagy, including criteria of OXIdative stress, APOPTOsis and autoPHAGY, associated with mitochondrial and peroxisomal dysfunction, which is counteracted by RSV, QCT, and API reinforcing the interest for these polyphenols in prevention of diseases associated with increased 7KC levels.
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In murine N2 neuronal cells treated with 7-ketocholesterol, the polyphenols resveratrol, quercetin, and apigenin reduce oxidative stress, apoptosis, autophagy, mitochondrial and peroxisomal dysfunction.
“These effects were reduced after the treatment of N2 cells with the polyphenols, resveratrol, quercetin and apigenin [120].”
From Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing (2021) · cites this paper as [120]
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Mediterranean Diet as an Antioxidant: The Impact on Metabolic Health and Overall Wellbeing
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- Authors
- Yammine, A., Zarrouk, A., Nury, T., Vejux, A., Latruffe, N., Vervandier-Fasseur, D., Samadi, M., Mackrill, J. J., Greige-Gerges, H., Auezova, L., & Lizard, G.
- Affiliations
- Inserm (FR)
- University of Monastir (TN)
- Team Bio-peroxIL, “Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism” (EA7270), University Bourgogne Franche-Comté, Inserm, 21000 Dijon, France
- Team OCS, Institute of Molecular Chemistry of University of Burgundy (ICMUB UMR CNRS 6302), University of Bourgogne Franche-Comté, 21000 Dijon, France
- Laboratoire de Chimie et Physique - Approche Multi-échelle des Milieux Complexes (FR)
- University College Cork (IE)
- Bioactive Molecules Research Laboratory, Doctoral School of Sciences and Technologies, Faculty of Sciences, Lebanese University, Fanar, Jdeidet P.O. Box 90656, Lebanon
- Lebanese University (LB)
- Corresponding author
- Lizard, Gérard
- ORCID
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2020-10-23
- Volume
- 9
- Issue
- 11
- Pages
- 2346
- ISSN
- 2073-4409 (ISSN-L)
- PMC
- PMC7690753
- OpenAlex
- W3094150982
- Cited by
- 79
- References
- 119
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 16 · 2023: 10 · 2022: 21 · 2021: 11 · 2020: 2
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cells (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- dietary polyphenols, resveratrol, quercetin, apigenin, 7-ketocholesterol, cholesterol oxidation, oxidative stress, apoptosis, autophagy, neuroprotection, mitochondrial dysfunction, peroxisome biogenesis, Nrf2, AMPK, SIRT1, PGC-1α, ABCD3, neurodegenerative diseases
- MeSH terms
- Resveratrol, Animals, Autophagy, Cell Line, Dose-Response Relationship, Drug, Humans, Ketocholesterols, Mitochondria, Neurons, Quercetin, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Neurodegenerative Diseases, Peroxisomes, Apigenin, Mice, Polyphenols
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