Integrative metabolomic and transcriptomic profiling uncovers the therapeutic mechanism of Qi Fu Yin in diabetic encephalopathy.

ETHNOPHARMACOLOGICAL RELEVANCE Qi Fu Yin (QFY), a formulation derived from the "Jingyue Quanshu,"is reputed for its ability to tonify qi, nourish blood, replenish essence and marrow, and enhance cognitive functions. Clinical studies have demonstrated its significant efficacy in ameliorating cognitive impairments such as amnesia and dementia. Nevertheless, the therapeutic effects and mechanisms of QFY on cognitive dysfunction related to diabetic encephalopathy (DE) still require significant and in-depth research.

Aim

OF THE STUDY This study aims to elucidate the efficacy and underlying mechanisms of QFY in the treatment of DE.

Methods

A DE model in C57BL/6J mice was established using a high-fat diet combined with intraperitoneal injection of streptozotocin. The improving effects of QFY on glucose and lipid metabolism disorders, cognitive dysfunction, and nerve damage in DE mice were systematically evaluated through behavioral experiments, biochemical indicator detection, and pathological staining of hippocampal tissues. The core regulatory pathways were identified using combined transcriptomic and metabolomic analyses. Additionally, RT-qPCR, Western blotting, immunofluorescence, and a high glucose-induced HT22 cell injury model were employed to verify the molecular mechanism of the AMPK/mTOR signaling pathway in regulating autophagy both in vivo and in vitro.

Results

QFY can significantly improve glucose and lipid metabolism disorders in DE mice, effectively reducing fasting blood glucose, glycated hemoglobin, and blood lipid levels. Meanwhile, it significantly increases SOD and GSH activities in hippocampal tissue, reduces MDA content, and alleviates oxidative stress damage. Behavioral and pathological test results show that QFY can significantly improve the spatial memory and cognitive function of DE mice, repair hippocampal neuronal structural damage, and inhibit neuronal apoptosis. Multi-omics integrated analysis confirmed that the AMPK/mTOR signaling pathway is the core pathway through which QFY intervenes in DE. In vivo and in vitro experiments further showed that QFY can activate the AMPK/mTOR pathway, upregulate the expression of the autophagy-related proteins Beclin1 and LC3, reduce p62 levels, and effectively inhibit high glucose-induced apoptosis by activating autophagy.

Conclusions

QFY can enhance autophagy by activating the AMPK/mTOR signaling pathway, improve glucose and lipid metabolism disorders, reduce oxidative stress damage in DE mice, inhibit hippocampal neuron apoptosis, and thereby alleviate cognitive dysfunction associated with DE. This provides a new experimental basis for the treatment of diabetic encephalopathy with Traditional Chinese Medicine.