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Formononetin attenuates H2O2-induced cell death through decreasing ROS level by PI3K/Akt-Nrf2-activated antioxidant
Mayuko Sugimoto1, Risa Ko1, Hiromi Goshima1
1Department of Pathobiochemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.
Abstract:
Formononetin is an isoflavone, found in herbs like Trifolium pratense, which executes a variety of physiological activities including anti-neurodegenerative effect. However, the molecular mechanism of formononetin-mediated neuroprotection remains unclear. In this study, we investigated the protective effect of formononetin on hydrogen peroxide (H2O2)-induced death of human neuroblastoma SH-SY5Y cells and its underlying molecular mechanism. Formononetin suppressed H2O2-induced cytotoxicity. H2O2-induced increase in the intracellular reactive oxygen species (ROS) levels was decreased by formononetin, together with the enhanced expression of the antioxidant genes. H2O2-induced elevation of the Bax/Bcl-2 ratio and cleaved caspase-3 and caspase-7 levels were lowered by formononetin treatment. Moreover, formononetin repressed H2O2-induced phosphorylation of mitogen-activated protein kinases (MAPKs). Nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA decreased antioxidant gene expression and elevated the H2O2-induced ROS level in the formononetin-treated cells. Furthermore, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling is involved in the activation of the nuclear translocation of Nrf2. These results indicate that the neuroprotective effect of formononetin against H2O2-induced cell death is due to a decrease in the ROS level with the enhanced expression of the antioxidant genes through activation of the PI3K/Akt-Nrf2 signaling. In addition, formononetin suppressed apoptosis through inhibition of phosphorylation of MAPKs in SH-SY5Y cells. Thus, formononetin is a potential therapeutic agent for the treatment of neurodegenerative diseases.
Insights
Formononetin protects against neurodegeneration by reducing oxidative stress and apoptosis. It activates the PI3K/Akt-Nrf2 pathway, enhancing antioxidant gene expression and inhibiting MAPK phosphorylation.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Formononetin, an isoflavone from Trifolium pratense, exhibits physiological activities, including potential anti-neurodegenerative effects.
- The precise molecular mechanisms underlying formononetin's neuroprotective properties are not fully elucidated.
Purpose of the Study:
- To investigate the protective effects of formononetin against hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells.
- To elucidate the molecular pathways involved in formononetin-mediated neuroprotection.
Main Methods:
- Cell viability assays to assess cytotoxicity.
- Measurement of intracellular reactive oxygen species (ROS) levels.
- Analysis of antioxidant gene expression.
- Western blotting to evaluate protein levels and phosphorylation states (Bax, Bcl-2, caspase-3, caspase-7, MAPKs, Nrf2, PI3K, Akt).
- RNA interference (siRNA) targeting Nrf2.
Main Results:
- Formononetin significantly reduced H2O2-induced cytotoxicity and intracellular ROS levels.
- Formononetin enhanced the expression of antioxidant genes, partly via the PI3K/Akt-Nrf2 signaling pathway.
- Formononetin suppressed apoptosis by lowering the Bax/Bcl-2 ratio and inhibiting caspase-3 and caspase-7 cleavage.
- Formononetin repressed H2O2-induced MAPK phosphorylation, and Nrf2 activation was crucial for its antioxidant effects.
Conclusions:
- Formononetin confers neuroprotection against H2O2-induced cell death by decreasing ROS and enhancing antioxidant gene expression through PI3K/Akt-Nrf2 signaling.
- Formononetin also inhibits apoptosis via MAPK pathway modulation in SH-SY5Y cells.
- Formononetin demonstrates potential as a therapeutic agent for neurodegenerative diseases.
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