Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl Species
Precursors of advanced glycation endproducts, namely, reactive carbonyl species (RCSs), are aging biomarkers that contribute to cell death. However, the impact of RCSs on ferroptosis—an iron-dependent form of cell death—in skin cells remains unknown. Herein, we constructed a cellular model (with hum...
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MDPI AG
2023-10-01
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| Series: | Nutrients |
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| Online Access: | https://www.mdpi.com/2072-6643/15/21/4565 |
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| author | Huifang Li Ni Deng Tess Puopolo Xian Jiang Navindra P. Seeram Chang Liu Hang Ma |
| author_facet | Huifang Li Ni Deng Tess Puopolo Xian Jiang Navindra P. Seeram Chang Liu Hang Ma |
| author_sort | Huifang Li |
| collection | DOAJ |
| description | Precursors of advanced glycation endproducts, namely, reactive carbonyl species (RCSs), are aging biomarkers that contribute to cell death. However, the impact of RCSs on ferroptosis—an iron-dependent form of cell death—in skin cells remains unknown. Herein, we constructed a cellular model (with human keratinocyte; HaCaT cells) to evaluate the cytotoxicity of the combinations of RCSs (including glyoxal; GO and methyglyoxal; MGO) and erastin (a ferroptosis inducer) using bioassays (measuring cellular lipid peroxidation and iron content) and proteomics with sequential window acquisition of all theoretical mass spectra. Additionally, a data-independent acquisition approach was used to characterize RCSs’ and erastin’s molecular network including genes, canonical pathways, and upstream regulators. Using this model, we evaluated the cytoprotective effects of two dietary flavonoids including cannflavins A and B against RCSs and erastin-induced cytotoxicity in HaCaT cells. Cannflavins A and B (at 0.625 to 20 µM) inhibited ferroptosis by restoring the cell viability (by 56.6–78.6% and 63.8–81.1%) and suppressing cellular lipid peroxidation (by 42.3–70.2% and 28.8–63.6%), respectively. They also alleviated GO + erastin- or MGO + erastin-induced cytotoxicity by 62.2–67.6% and 56.1–69.3%, and 35.6–54.5% and 33.8–62.0%, respectively. Mechanistic studies supported that the cytoprotective effects of cannflavins A and B are associated with their antioxidant activities including free radical scavenging capacity and an inhibitory effect on glycation. This is the first study showing that cannflavins A and B protect human keratinocytes from RCSs + erastin-induced cytotoxicity, which supports their potential applications as dietary interventions for aging-related skin conditions. |
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| spelling | doaj.art-ca2ebc0851834d22b8c7ffb41a08e99f2023-11-10T15:09:38ZengMDPI AGNutrients2072-66432023-10-011521456510.3390/nu15214565Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl SpeciesHuifang Li0Ni Deng1Tess Puopolo2Xian Jiang3Navindra P. Seeram4Chang Liu5Hang Ma6Bioactive Botanical Research Laboratory, Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USABioactive Botanical Research Laboratory, Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USABioactive Botanical Research Laboratory, Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USADepartment of Dermatology, Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, ChinaBioactive Botanical Research Laboratory, Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USABioactive Botanical Research Laboratory, Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USABioactive Botanical Research Laboratory, Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USAPrecursors of advanced glycation endproducts, namely, reactive carbonyl species (RCSs), are aging biomarkers that contribute to cell death. However, the impact of RCSs on ferroptosis—an iron-dependent form of cell death—in skin cells remains unknown. Herein, we constructed a cellular model (with human keratinocyte; HaCaT cells) to evaluate the cytotoxicity of the combinations of RCSs (including glyoxal; GO and methyglyoxal; MGO) and erastin (a ferroptosis inducer) using bioassays (measuring cellular lipid peroxidation and iron content) and proteomics with sequential window acquisition of all theoretical mass spectra. Additionally, a data-independent acquisition approach was used to characterize RCSs’ and erastin’s molecular network including genes, canonical pathways, and upstream regulators. Using this model, we evaluated the cytoprotective effects of two dietary flavonoids including cannflavins A and B against RCSs and erastin-induced cytotoxicity in HaCaT cells. Cannflavins A and B (at 0.625 to 20 µM) inhibited ferroptosis by restoring the cell viability (by 56.6–78.6% and 63.8–81.1%) and suppressing cellular lipid peroxidation (by 42.3–70.2% and 28.8–63.6%), respectively. They also alleviated GO + erastin- or MGO + erastin-induced cytotoxicity by 62.2–67.6% and 56.1–69.3%, and 35.6–54.5% and 33.8–62.0%, respectively. Mechanistic studies supported that the cytoprotective effects of cannflavins A and B are associated with their antioxidant activities including free radical scavenging capacity and an inhibitory effect on glycation. This is the first study showing that cannflavins A and B protect human keratinocytes from RCSs + erastin-induced cytotoxicity, which supports their potential applications as dietary interventions for aging-related skin conditions.https://www.mdpi.com/2072-6643/15/21/4565skin-agingferroptosisreactive carbonyl speciesproteomicscell deathkeratinocytes |
| spellingShingle | Huifang Li Ni Deng Tess Puopolo Xian Jiang Navindra P. Seeram Chang Liu Hang Ma Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl Species Nutrients skin-aging ferroptosis reactive carbonyl species proteomics cell death keratinocytes |
| title | Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl Species |
| title_full | Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl Species |
| title_fullStr | Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl Species |
| title_full_unstemmed | Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl Species |
| title_short | Cannflavins A and B with Anti-Ferroptosis, Anti-Glycation, and Antioxidant Activities Protect Human Keratinocytes in a Cell Death Model with Erastin and Reactive Carbonyl Species |
| title_sort | cannflavins a and b with anti ferroptosis anti glycation and antioxidant activities protect human keratinocytes in a cell death model with erastin and reactive carbonyl species |
| topic | skin-aging ferroptosis reactive carbonyl species proteomics cell death keratinocytes |
| url | https://www.mdpi.com/2072-6643/15/21/4565 |
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