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Mulberry leaf flavonoid extract inhibits high glucose-induced ferroptosis by regulating the PI-3K/Akt/Nrf2/GPX4
Fan Yang1, Liang Li2, Tao Chai2
1Department of Endocrinology, Nanbu County People's Hospital, Nanchong City, Sichuan Province, 637300, China.
Objective:
To explore the inhibitory effects of mulberry leaf flavonoid extract (MFE) on high glucose-induced diabetic encephalopathy (DE) in a cell model, and to investigate the underlying mechanisms combined with network pharmacology prediction and experimental validation.
Methods:
A DE cell model was established by chronic high glucose stimulation of HT22 mouse hippocampal neuronal cells. Following intervention with MFE, cell viability, advanced glycation end products (AGEs) content, and ferroptosis-related indices were detected. Network pharmacology was used to screen potential signaling pathways and key targets of MFE, while Western blotting validated the expression of proteins related to the screened pathways and targets.
Results:
Network pharmacology screening identified Akt1, ALB, TNF, IL-1B, and IL-6 as the top-ranked targets. Molecular docking confirmed stable binding between major MFE components and these potential targets. MFE treatment markedly upregulated ferritin heavy chain (FTH) and ferroportin (FPN) levels while decreasing transferrin receptor (TFRC) levels, attenuating iron overload in DE cells. It also suppressed AGEs accumulation, which activated the downstream PI3K/Akt/Nrf2/SLC7A11/GPX4 ferroptosis regulatory pathway to mitigate oxidative stress and inhibit ferroptosis. Additionally, MFE activated Akt, leading to p38 MAPK deactivation, reduced Bax/Bcl-2 ratio, and decreased Caspase-3 levels, blocking the apoptosis pathway. It alleviated inflammatory injury by suppressing the p38 MAPK/NF-κB pathway, thereby reducing TNF-α, IL-1β, and IL-6 protein levels.
Conclusion:
MFE inhibits ferroptosis by upregulating the PI3K/Akt/Nrf2/GPX4 signaling pathway. This study provides valuable insights into the therapeutic application of MFE for DE.
Insights
Mulberry leaf flavonoid extract (MFE) effectively treats diabetic encephalopathy (DE) by inhibiting ferroptosis and apoptosis. MFE upregulates the PI3K/Akt/Nrf2/GPX4 pathway, offering therapeutic potential for DE.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Diabetic encephalopathy (DE) is a debilitating condition characterized by neuronal damage.
- High glucose levels induce oxidative stress, ferroptosis, and inflammation in the brain.
- Effective therapeutic strategies for DE are urgently needed.
Purpose of the Study:
- To investigate the neuroprotective effects of mulberry leaf flavonoid extract (MFE) on a high glucose-induced DE cell model.
- To elucidate the underlying molecular mechanisms of MFE action, including its impact on ferroptosis, apoptosis, and inflammation.
- To combine network pharmacology predictions with experimental validation for a comprehensive understanding.
Main Methods:
- Established a DE cell model using HT22 mouse hippocampal neuronal cells exposed to chronic high glucose.
- Treated cells with MFE and assessed cell viability, advanced glycation end products (AGEs), and ferroptosis markers.
- Employed network pharmacology to identify MFE targets and pathways, followed by Western blotting for validation.
Main Results:
- MFE treatment significantly reduced AGEs accumulation and iron overload in DE cells.
- MFE upregulated ferritin heavy chain (FTH) and ferroportin (FPN), while downregulating transferrin receptor (TFRC).
- MFE activated the PI3K/Akt/Nrf2/GPX4 pathway, inhibiting ferroptosis and oxidative stress.
- MFE suppressed apoptosis by modulating Bax/Bcl-2 ratio and Caspase-3 activity.
- MFE alleviated inflammation by inhibiting the p38 MAPK/NF-κB pathway, reducing pro-inflammatory cytokines.
Conclusions:
- MFE demonstrates significant neuroprotective effects against high glucose-induced DE.
- The primary mechanism involves the upregulation of the PI3K/Akt/Nrf2/GPX4 signaling pathway, inhibiting ferroptosis.
- MFE also mitigates apoptosis and inflammation, highlighting its therapeutic potential for DE.