Glycyrrhizic acid combined with human adipose-derived MSCs synergistically alleviates the MPP+/MPTP-induced parkinson's disease by inducing autophagy through PI3K/AKT/HIF-1α pathway.

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AimsEmerging research highlights the considerable therapeutic promise of glycyrrhizic acid (GA) and stem cells used separately for Parkinson's disease (PD). Nevertheless, the combined effects of GA and adipose-derived mesenchymal stem cells (ADSCs) in PD models have not been thoroughly investigated. This research is designed to evaluate the therapeutic potential of GA combined with ADSCs in vitro and in vivo, and to analyze the underlying molecular mechanisms.Main methodsIn vitro experiments were performed in SH-SY5Y cell. In vivo experiments were performed in C57BL/6 mice.Key findingsIn comparison to other treatment groups, the combination of GA and ADSCs exhibited improved therapeutic effects in vitro. RNA sequencing analysis revealed involvement of autophagy and the PI3K/AKT/HIF-1α signaling pathway in the treatment. In follow-up research, the combination of GA and ADSCs markedly increased the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR proteins in vitro following 1-methyl-4-phenylpyridinium (MPP+) exposure. Besides, the combined treatment downregulated the LC3II/LC3I expression ratio and Beclin-1 expression levels while upregulating p62, HIF-1α, and VEGFA expression levels. Similar to 3-MA, results from western blot, transmission electron microscopy (TEM) and immunofluorescence staining (IF) indicated that the combined treatment significantly reduced autophagy. However, treatment with the PI3K inhibitor (LY294002) reversed these increases in the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR, as well as the levels of p62, HIF-1α, and VEGFA. Moreover, LY294002 significantly impaired the autophagy-suppressing effects of the combination treatment. Finally, the combination of GA and ADSCs ameliorated behavioral deficits and pathological damage to dopaminergic neurons in PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).SignificanceThe combination of GA and ADSCs displayed remarkable neuroprotective effects in vitro and in vivo. The underlying mechanism involves the regulation of autophagy via the PI3K/AKT/HIF-1α signaling pathway.

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