Genistein Suppresses Ox-LDL-elicited Oxidative Stress and Senescence in HUVECs through the SIRT1-p66shc-Foxo3a Pathways
Abstract
The anti‐senescence function of genistein is related to inhibiting oxidative stress, however, the mechanism has not been clarified. The present study aimed to explore the effects of genistein on oxidized low‐density lipoprotein (ox‐LDL)‐induced endothelial senescence and the role of the sirtuin‐1 (SIRT1)—66‐kDa Src homology 2 domain‐containing protein (p66Shc)–forkhead box protein O3 (Foxo3a) pathways in the process. In this paper, human umbilical vein endothelial cells were pretreated with 1000 nM genistein for 30 min and then incubated with 50 mg/L ox‐LDL for another 12 h; meanwhile, the functions of adenovirus‐mediated overexpression of p66shc and small interfering RNA‐mediated silencing of SIRT1 were investigated. Results showed that genistein pretreatment alleviated ox‐LDL‐induced mitochondrial reactive oxygen species, the levels of oxidatively modified DNA (8‐OHdG) and pai‐1, and the activity of SA‐β‐gal, which was associated with mitigating p66shc. Further studies indicated the inhibitory effect of genistein on p66shc was correlated with suppressing the acetylation and phosphorylation of p66shc, and ameliorating its mitochondrial translocation by activating SIRT1. Moreover, the inactivated p66shc could enhance the activity of Foxo3a via restraining the phosphorylation and triggering nucleus accumulation. The study demonstrates genistein could prevent ox‐LDL‐induced mitochondrial oxidative stress and senescence through the SIRT1–p66shc–Foxo3a pathways.
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Genistein reduces OS-induced senescence by mitigating levels of mitochondrial ROS and DNA oxidation marker 8-OHdG, and by upregulating the SIRT1-FOXO3 axis.
“Mechanistically, genistein reduces OS-induced senescence by mitigating the levels of mitochondrial ROS and of the DNA oxidation marker 8-OHdG, as well as by upregulating the SIRT1-FOXO3 axis, which is known to prevent aging [278].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [278]
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- Authors
- Zhang, H., Pang, X., Yu, H., & Zhou, H.
- Affiliations
- Shanxi Medical University (CN)
- National Key Disciplines, Key Laboratory for Cellular Physiology of Ministry of Education Shanxi Medical University Taiyuan Shanxi PR China
- Corresponding author
- Zhang, Huaping
- Venue
- Journal of Biochemical and Molecular Toxicology
- Publisher
- Wiley
- Published
- 2021-10-31
- Volume
- 36
- Issue
- 1
- Pages
- e22939-e22939
- ISSN
- 0887-2082 (ISSN-L)
- 1095-6670
- 1099-0461
- OpenAlex
- W3210554726
- Cited by
- 18
- References
- 47
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 2 · 2022: 2
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Biochemical and Molecular Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Shanxi Province (201801D121317)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Keywords
- genistein, oxidized LDL, endothelial cell senescence, oxidative stress, SIRT1, p66Shc, FOXO3, mitochondrial reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, SA-β-galactosidase, isoflavones, endothelial dysfunction
- MeSH terms
- Forkhead Box Protein O3, Src Homology 2 Domain-Containing, Transforming Protein 1, Humans, Lipoproteins, LDL, Signal Transduction, Cellular Senescence, Oxidative Stress, Genistein, Sirtuin 1, Human Umbilical Vein Endothelial Cells
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