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Cyanidin-3-O-glucoside counters the response to TNF-alpha of endothelial cells by activating Nrf2 pathway
Antonio Speciale1, Sirajudheen Anwar, Raffaella Canali
1Department of Drug Sciences and Health Products, University of Messina, Messina, Italy.
Scope:
Many dietary phytochemicals have been shown able to prevent a large spectrum of diseases, including cardiovascular disorders, with a mechanism commonly ascribed to an antioxidant effect. However, these in vivo beneficial effects are unlikely to be explained on the base of this mechanism. The discovery of specific genes regulated by the antioxidant responsive element (ARE) affected by antioxidants/electrophiles, led to the hypothesis that some phytochemicals may act as modulators of signal transduction pathways. The aim of the study was to investigate if in vitro pharmacological activation of Nrf2 pathway by cyanidin-3-O-glucoside (C3G) may be involved in its antiatherogenic effects.
Methods And Results:
Herein, we investigated the in vitro effects of C3G on cell signaling pathways in human umbilical vein endothelial cells (HUVECs) challenged with tumor necrosis factor-α (TNF-α). Pretreatment with C3G prevented oxidative stress, improved antioxidant systems, and activated Nrf2/ARE pathway, at baseline and after TNF-α treatment. Furthermore, we demonstrated the involvement of specific mitogen-activated protein kinases (MAPKs) (ERK1/2) in C3G induction of Nrf2/ARE pathway. Finally, the inactivation of ERK1/2 activity by the inhibitor PD98059 abolished the increase of Nrf2 nuclear accumulation induced by C3G, and also increased NF-κB p65 nuclear translocation in TNF-α challenged cells.
Conclusion:
Our data confirm the hypothesis that natural Nrf2 and HO-1 inducers, such as C3G and other dietary phytochemicals, might be a potential therapeutic strategy to protect vascular system against various stressors preventing several pathological conditions.
Insights
Cyanidin-3-O-glucoside (C3G) activates the Nrf2 pathway, enhancing antioxidant defenses and offering protection against vascular stress. This highlights C3G
Area of Science:
- Molecular Biology
- Cell Signaling
- Cardiovascular Research
Background:
- Dietary phytochemicals show disease prevention, but antioxidant effects alone don't fully explain in vivo benefits.
- Specific genes regulated by the antioxidant responsive element (ARE) are influenced by antioxidants/electrophiles.
- Phytochemicals may act as modulators of signal transduction pathways, offering a novel therapeutic avenue.
Purpose of the Study:
- To investigate if cyanidin-3-O-glucoside (C3G) pharmacologically activates the Nrf2 pathway in vitro.
- To determine C3G's role in its antiatherogenic effects.
- To explore the involvement of signaling pathways in C3G's action.
Main Methods:
- Investigated in vitro effects of C3G on human umbilical vein endothelial cells (HUVECs) stimulated with tumor necrosis factor-α (TNF-α).
- Assessed oxidative stress, antioxidant systems, and Nrf2/ARE pathway activation.
- Utilized mitogen-activated protein kinases (MAPKs) inhibitors (PD98059) to study pathway involvement.
Main Results:
- C3G pretreatment prevented oxidative stress and enhanced antioxidant systems in HUVECs.
- C3G activated the Nrf2/ARE pathway, involving ERK1/2 signaling.
- ERK1/2 inhibition abolished C3G-induced Nrf2 nuclear accumulation and increased NF-κB p65 translocation.
Conclusions:
- Natural Nrf2 and HO-1 inducers like C3G are potential therapeutic agents.
- C3G demonstrates protective effects against vascular stressors.
- These findings support C3G and similar phytochemicals for preventing pathological vascular conditions.
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