Paeoniflorin Effect of Schwann Cell-Derived Exosomes Ameliorates Dorsal Root Ganglion Neurons Apoptosis through IRE1α Pathway

Abstract

Background. Diabetic peripheral neuropathy (DPN) is a common complication of diabetes but its pathogenesis is not fully clarified. Endoplasmic reticulum (ER) stress has been confirmed to be involved in the development of DPN. Dorsal root ganglion neuron (DRGn) is the target cell of DPN injure in the peripheral neurons system. Schwann cell (SCs)-derived exosomes (SC-EXOs) can carry IRE1α signal transduction factors in ER stress to DRGn. The aim of this study is to investigate the effect of SC-EXOs treated with paeoniflorin (PF) on DRGn stimulated by high glucose. Methods. SCs were divided into Control group (Control), 150 mM glucose group (HG), high osmotic pressure group (HOP), and low, middle, and high dose PF group (PF1, PF10, and PF100). Exosomes were obtained from SCs by ultracentrifugation and identified according to marker proteins, including CD63, Alix, Hsp70, and TSG101. ER stress initiating factor GRP78, the IRE1α pathway information transmission factor IRE1α, and the phosphorylation level of IRE1α were detected by Western blot, DRGn is divided into Control group (Control), 50 mM glucose group + Control exosomes group (HG + EXOs Control), 50 mM glucose group (HG), and 50 mM glucose group + administration exosomes group (HG + EXOs PF1, HG + EXOs PF10, and HG + EXOs PF100); ER morphology of primary DRGn was observed by using the transmission electron microscope, the level of DRGn apoptosis was analyzed by TUNEL, and the downstream proteins of ER stress including CHOP, XBP1S, JNK, and p-JNK in DRG and the expression of apoptosis-related proteins Bcl-2, Bax, Caspase-3, and Caspase-12 were measured by Western blot. Results. Compared with the exosomes in the HG group, the exosomes after the intervention of PF can significantly reduce the expression of GRP78, IRE1α, and the phosphorylation level of IRE1α P < 0.05 ; compared with the DRGn in the HG group, the SC-EXOs treated with PF could regulate the expression of proteins downstream of IRE1α pathway in ER stress ( P < 0.05 or P < 0.01 ), improve the morphological integrity of ER, and reduce apoptosis in DRGn ( P < 0.05 or P < 0.01 ). Conclusion. PF regulates the information of ER stress carried by SC-EXOs and further affects downstream of IRE1α pathway in DRGn, thus reducing ER stress-induced apoptosis. PF can interfere with DPN through affecting information communication carried by EXOs between SCs and DRGn.

Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications

“…These interactions are vital for preventing neuropathy in DM. 190 The exosomes isolated from mesenchymal stem cells demonstrate potential in ameliorating diabetic peripheral neuropathy. 191 The underlying molecular pathways affected by these exosomes are of importance.…”

“…Various molecular pathways, including VEGF, IRE1α, Bax, caspase-3, and NLRP3, are affected by the exosomes derived from different sources such as adipose stem cells, mesenchymal cells, and macrophages. 190,194,200,202,217,219,[241][242][243][244][245][246][247][248][249] Table 3 provides a summary of exosomes and their application in alleviation of diabetic complications. Figure 4 demonstrates the potential of exosomes in alleviating diabetic complications.…”

Paeoniflorin Ameliorates BiPN by Reducing IL6 Levels and Regulating PARKIN-Mediated Mitochondrial Autophagy

“…Paeoniflorin has been shown to significantly alleviate PN caused by diabetes and paclitaxel. 24,59,60 The present study is the first to report the protective effect of paeoniflorin on bortezomib-induced peripheral neuropathy. In the present study, bortezomib was used to induce peripheral neuropathy in C57BL/6J mice, and the effects of paeoniflorin on inflammation and autophagy were investigated in a model of peripheral neuropathy.…”

Understanding exosomes: Part 2—Emerging leaders in regenerative medicine

“…682 Exosomes have been shown to possess an ability to lower apoptosis in neurons. 683 Another DM consequence that leads to end-stage renal disease is nephropathy. 685 Nephropathy occurs in 25% of patients and develops for a number of reasons.…”