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Objective <p>To explore the effect of ginsenoside Rg2 (G-Rg2) targeting pyruvate dehydrogenase E1 component subunit alpha (PDHE1 α) on its downstream energy metabolism to repair damaged hippocampal neurons.</p> Methods <p>The binding affinity between G-Rg2 and PDHE1 α was obtained by molecular docking (MD) and surface plasmon resonance (SPR). The thermal stability of Rg2 binding to PDHE1 α protein was evaluated by cellular thermal shift assay (CETSA), and the binding of Rg2 to PDHE1 α protein was further confirmed by isothermal dose-response curve. The mouse hippocampal neuronal cell line (HT22) was divided into 2 main groups: a PDHE1 α transfection control group and a PDHE1 α silencing group. Each main group was further subdivided into 3 treatment groups: a normal group (untreated), a high-glucose injury model group, and a Rg2 adminis0tration group. The downstream molecules and metabolites of PDHE1 α such as adenosine triphosphate (ATP), reactive oxygen species (ROS), acetyl coenzyme A (acetyl-CoA), and the oxidized/reduced ratio of nicotinamide adenine dinucleotide (NAD<sup>+</sup>/NADH ratio) were measured. The energy metabolism patterns of each group were analyzed using the hippocampus bioenergy analyzer to further confirm the interaction between Rg2 and PDHE1 α and the biological effect of the interaction.</p> Results <p>MD and SPR techniques found that G-Rg2 directly bound to the target protein PDHE1 α and significantly improved its thermal stability. Isothermal dose-response results were consistent with these findings. The high glucose-induced HT22 cell injury model showed abnormal phenotypes including decreased PDH enzyme activity, increased ROS, decreased ATP production, an imbalanced NAD<sup>+</sup>/NADH ratio, decreased acetyl-CoA production, and altered glucose metabolism. After G-Rg2 intervention, different degrees of metabolic recovery were observed (<i>P</i>&lt;0.05 or <i>P</i>&lt;0.01). When PDHE1 α was silenced, the silenced group showed a similar metabolic damage phenotype induced by high glucose, compared with the normal group. After PDHE1 α silencing, glucose modeling further aggravated the damage. In the injury model of PDHE1 α silencing with glucose induction, G-Rg2 showed different degrees of metabolic recovery after intervention (<i>P</i>&lt;0.05 or <i>P</i>&lt;0.01).</p> Conclusion <p>PDHE1 α can be used as a direct cell target for G-Rg2 to treat high glucose-injured neurons, which can provide data support for the protein activity of PDHE1 α and the pharmacological activity of G-Rg2 in improving neurodegenerative diseases.</p>

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Ginsenoside Rg2 Targeting PDHE1 α to Improve High Glucose-Induced Hippocampal Neuronal Damage Based on CETSA Experiment

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Lian-lian Zhu,
  • Dan-feng Fan,
  • Qi-ge Wang,
  • Tong Lu,
  • Li-bin Zhan

摘要

Objective

To explore the effect of ginsenoside Rg2 (G-Rg2) targeting pyruvate dehydrogenase E1 component subunit alpha (PDHE1 α) on its downstream energy metabolism to repair damaged hippocampal neurons.

Methods

The binding affinity between G-Rg2 and PDHE1 α was obtained by molecular docking (MD) and surface plasmon resonance (SPR). The thermal stability of Rg2 binding to PDHE1 α protein was evaluated by cellular thermal shift assay (CETSA), and the binding of Rg2 to PDHE1 α protein was further confirmed by isothermal dose-response curve. The mouse hippocampal neuronal cell line (HT22) was divided into 2 main groups: a PDHE1 α transfection control group and a PDHE1 α silencing group. Each main group was further subdivided into 3 treatment groups: a normal group (untreated), a high-glucose injury model group, and a Rg2 adminis0tration group. The downstream molecules and metabolites of PDHE1 α such as adenosine triphosphate (ATP), reactive oxygen species (ROS), acetyl coenzyme A (acetyl-CoA), and the oxidized/reduced ratio of nicotinamide adenine dinucleotide (NAD+/NADH ratio) were measured. The energy metabolism patterns of each group were analyzed using the hippocampus bioenergy analyzer to further confirm the interaction between Rg2 and PDHE1 α and the biological effect of the interaction.

Results

MD and SPR techniques found that G-Rg2 directly bound to the target protein PDHE1 α and significantly improved its thermal stability. Isothermal dose-response results were consistent with these findings. The high glucose-induced HT22 cell injury model showed abnormal phenotypes including decreased PDH enzyme activity, increased ROS, decreased ATP production, an imbalanced NAD+/NADH ratio, decreased acetyl-CoA production, and altered glucose metabolism. After G-Rg2 intervention, different degrees of metabolic recovery were observed (P<0.05 or P<0.01). When PDHE1 α was silenced, the silenced group showed a similar metabolic damage phenotype induced by high glucose, compared with the normal group. After PDHE1 α silencing, glucose modeling further aggravated the damage. In the injury model of PDHE1 α silencing with glucose induction, G-Rg2 showed different degrees of metabolic recovery after intervention (P<0.05 or P<0.01).

Conclusion

PDHE1 α can be used as a direct cell target for G-Rg2 to treat high glucose-injured neurons, which can provide data support for the protein activity of PDHE1 α and the pharmacological activity of G-Rg2 in improving neurodegenerative diseases.