Neferine modulates IGF-1R/Nrf2 signaling in doxorubicin treated H9c2 cardiomyoblasts
Lohanathan Bharathi Priya1, Rathinasamy Baskaran2, Chih-Yang Huang3,4,5
1Translational Research Laboratory, Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, Tamil Nadu, India.
Abstract:
Doxorubicin (DOX) induced cardiotoxicity is a major problem during chemotherapy of cancers. DOX-mediated suppression of type 1 IGF receptor (IGF-1R) signaling leads to cardiac dysfunction. Neferine, a bisbezylisoquinoline alkaloid from the seed embryos of Nelumbo nucifera Gaertn possesses a distinct range of pharmacological properties. Herewith, the present study attempts to elucidate the protective role of neferine against DOX induced toxicity in H9c2 rat cardiomyoblast cell line model. DOX-treated H9c2 cells significantly increased mitochondrial superoxide generation, depleted cellular antioxidant status, suppressed the activation of IGF-1R signaling via PI3K/Akt/mTOR and induced autophagy by the activation of ULK1, Beclin1, Atg7, and LC3B. Neferine pre-treatment activated IGF-1R signaling, improved cellular antioxidant pool, increased the expression of down-stream targets of IGF-1R, such as PI3K/Akt/mTOR, inhibited mitochondrial superoxide generation and autophagy significantly with the induction of Nrf2 translocation and expressions of HO1 and SOD1. Our study suggests the use of neferine for amelioration of DOX-mediated cardiotoxicity.
Insights
Neferine protects against Doxorubicin (DOX)-induced cardiotoxicity by activating IGF-1R signaling and enhancing antioxidant status. This natural compound mitigates DOX-induced mitochondrial damage and autophagy in heart cells.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Toxicology
- Natural Product Chemistry
Background:
- Doxorubicin (DOX) chemotherapy can cause cardiotoxicity, a significant clinical challenge.
- DOX-induced cardiac dysfunction is linked to suppressed type 1 IGF receptor (IGF-1R) signaling.
- Neferine, a natural alkaloid from Nelumbo nucifera, has shown diverse pharmacological effects.
Purpose of the Study:
- To investigate the protective effects of neferine against DOX-induced cardiotoxicity.
- To elucidate the molecular mechanisms underlying neferine's cardioprotective action in a cellular model.
Main Methods:
- Utilized H9c2 rat cardiomyoblast cells as a model system.
- Assessed mitochondrial superoxide generation, cellular antioxidant status, and IGF-1R signaling pathway activation (PI3K/Akt/mTOR).
- Evaluated autophagy markers (ULK1, Beclin1, Atg7, LC3B) and Nrf2 pathway activation (Nrf2, HO1, SOD1).
Main Results:
- DOX treatment increased mitochondrial superoxide and autophagy while suppressing IGF-1R signaling.
- Neferine pre-treatment reversed DOX-induced effects by activating IGF-1R, enhancing antioxidants, and inhibiting mitochondrial damage and autophagy.
- Neferine promoted Nrf2 translocation and expression of antioxidant enzymes HO1 and SOD1.
Conclusions:
- Neferine demonstrates significant cardioprotective effects against Doxorubicin-induced toxicity.
- Neferine acts by restoring IGF-1R signaling, bolstering antioxidant defenses, and modulating autophagy.
- Neferine holds potential as a therapeutic agent to mitigate chemotherapy-induced cardiotoxicity.
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