MicroRNA-181a–2–3p shuttled by mesenchymal stem cell-secreted extracellular vesicles inhibits oxidative stress in Parkinson’s disease by inhibiting EGR1 and NOX4

Abstract

The current study investigated the physiological mechanisms by which extracellular vesicle (EV)-encapsulated miR-181a–2–3p derived from mesenchymal stem cells (MSCs) might mediate oxidative stress (OS) in Parkinson’s disease (PD). First, 6-hydroxydopamine (6-OHDA)-induced PD cell and mouse models were established, after which miR-181a–2–3p, EGR1, and NOX4 expression patterns were determined in SH-SY5Y cells and substantia nigra (SN) of PD mice. Next, the binding affinity among miR-181a–2–3p, EGR1, and NOX4 was identified using multiple assays. Gain- or loss-of-function experiments were further adopted to detect SH-SY5Y cell proliferation and apoptosis and to measure the levels of SOD, MDA, and ROS. Finally, the effects of miR-181a–2–3p from MSC-derived EVs in PD mouse models were also explored. It was found that miR-181a–2–3p was poorly expressed in 6-OHDA-induced SH-SY5Y cells, whereas miR-181a–2–3p from MSCs could be transferred into SH-SY5Y cells via EVs. In addition, miR-181a–2–3p could target and inhibit EGR1, which promoted the expression of NOX4. The aforementioned miR-181a–2–3p shuttled by MSC-derived EVs facilitated SH-SY5Y proliferation and SOD levels, but suppressed apoptosis and MDA and ROS levels by regulating EGR1 via inhibition of NOX4/p38 MAPK, so as to repress OS of PD. Furthermore, in PD mice, miR-181a–2–3p was carried by EVs from MSCs to alleviate apoptosis of dopamine neurons and OS, accompanied by increased expressions of α-syn and decreased 4-HNE in SN tissues. Collectively, our findings revealed that MSC-derived EV-loaded miR-181a–2–3p downregulated EGR1 to inhibit OS via the NOX4/p38 MAPK axis in PD.

Oxidative Stress and Extracellular Matrix Remodeling Are Signature Pathways of Extracellular Vesicles Released upon Morphine Exposure on Human Brain Microvascular Endothelial Cells

“…This biological pathway may be an EV signature pathway induced by morphine, reflecting the same changes in cells of origin. Some studies have already speculated on EVs functions in redox signaling and oxidative stress-related diseases such as neurologic, oncologic or cardiovascular pathologies [ 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. However, more studies are needed to confirm this hypothesis.…”

Recent advances of the mammalian target of rapamycin signaling in mesenchymal stem cells

“…When nearly 60% of dopaminergic neurons in the aubstantia nigra dense region are eliminated, Parkinsonian symptoms begin to appear ( Cooper et al, 2009 ). The occurrence of PD is related to many factors, such as ageing and oxidative stress ( Ma et al, 2022 ). It is estimated that approximately 12% of people 65 and older have PD ( Lan et al, 2017 ).…”

Role of the OTUB1/IRF7/NOX4 axis in oxidative stress injury and inflammatory responses in mice with Parkinson's disease

“…IRF7 promotes NOX4 expression IRF7 as a transcription factor can regulate the transcription of downstream target genes, and NOX4 has been reported to be upregulated in PD and associated with oxidative stress. 16,22 The JASPAR database predicted the binding of IRF7 to the NOX4 promoter (Fig. 5a).…”

“…NADPH oxidase 4 (NOX4) is one isoform of the NADPH oxidases that are the enzymatic source of ROS production in the central nervous system 15 . In concert with the p38 MAPK pathway, NOX4 contributes to OSI in PD 16 . Furthermore, the JASPAR database was indicative of the binding of IRF7 to the NOX4 promoter, hinting at a potential role of IRF7 in NOX4 transcription.…”

“…15 In concert with the p38 MAPK pathway, NOX4 contributes to OSI in PD. 16 Furthermore, the JASPAR database was indicative of the binding of IRF7 to the NOX4 promoter, hinting at a potential role of IRF7 in NOX4 transcription. However, whether IRF7 and NADPH were associated with the downstream of OTUB1 in PD has not been reported before.…”