Paeoniflorin Upregulates Mitochondrial Thioredoxin of Schwann Cells to Improve Diabetic Peripheral Neuropathy Indicated by 4D Label-Free Quantitative Proteomics

Abstract

Diabetic peripheral neuropathy (DPN) is a diabetic complication characterized by demyelination. The pathogenesis of DPN has not been fully elucidated, thus lacking therapies. In the current study, we aimed to confirm whether paeoniflorin (PF) could improve DPN by upregulating mitochondrial thioredoxin (Trx2) based on 4D Label-free proteomic experiments of Schwann cells (SCs) mitochondria. Firstly, PF increased the expression of mitochondrial processing peptidase α (Pmpca) and small ubiquitin-related modifier 1 (Sumo1) to increase mitochondrial protein processing of Trx2. Then, PF increased the protein expression of Trx reductase 2 (TrxR2) and peroxiredoxin 3 (Prx3), which belong to mitochondrial Trx systems. Accordingly, PF decreased mitochondrial reactive oxygen species (ROS) while increasing mtDNA and mitochondrial membrane potential to improve mitochondria function under high glucose environment. Furthermore, total glucosides of paeony capsules (TGP), containing more than 90% PF, increased the Trx2, TrxR2, and Prx3 levels in sciatic nerve of DPN rats, thus reducing demyelination as well as improving mechanical pain threshold, thermal pain threshold, motor nerve conduction velocity (MNCV), and sensor nerve conduction velocity (SNCV). Overall, these results suggest that PF could provide protection for DPN by upregulating Trx2.

Beneficial Effects of lncRNA-UC.360+ shRNA on Diabetic Cardiac Sympathetic Damage via NLRP3 Inflammasome-Induced Pyroptosis in Stellate Ganglion

“…Therefore, reducing the content of ROS to block the ROS-activated apoptotic pathway may be a new therapeutic target for diabetic autonomic neuropathy. 21 Our data showed that the content of ROS in the SG of DM rats was significantly increased, whereas lncRNA-UC.360+ shRNA treatment could reduce the ROS overproduction in DM rats, suggesting the beneficial effect of lncRNA-UC.360+ shRNA on reducing the ROS produced at high glucose in diabetes.…”

“…High glucose can prompt cells to produce excess ROS, which in turn regulates the activation of protein kinase C, MAPK, and various cytokines and transcription factors, resulting in enhanced expression of cell-injury molecules, which ultimately leads to sympathetic neuropathy in diabetes. Therefore, reducing the content of ROS to block the ROS-activated apoptotic pathway may be a new therapeutic target for diabetic autonomic neuropathy . Our data showed that the content of ROS in the SG of DM rats was significantly increased, whereas lncRNA-UC.360+ shRNA treatment could reduce the ROS overproduction in DM rats, suggesting the beneficial effect of lncRNA-UC.360+ shRNA on reducing the ROS produced at high glucose in diabetes.…”

Use of Monoterpenes as Potential Therapeutics in Diabetes Mellitus: A Prospective Review

“…Paeoniforin also has an action at the level of increasing the expression of mitochondrial processing peptidase α (PMPCA) and small ubiquitin 1 (Sumo1) which are responsible for increasing mitochondrial Trx2 (thioredoxin 2) protein processing and increasing Trx2 levels, TrxR2, and Prx3 in the sciatic nerve of rats with diabetic neuropathy, a severe consequence of diabetes mellitus, thereby reducing demyelination as well as improving mechanical pain threshold, thermal pain threshold, motor nerve conduction velocity (MNCV), and sensory nerve conduction velocity (SNCV). Overall, these results suggest that paeoniforin could provide protection for the diabetic neuropathy (ND) condition by regulating Trx2 [98]. Paeoniforin is, therefore, a natural glycoside with antihyperglycemic efect.…”

Proteomic analysis of extracellular vesicles from tick hemolymph and uptake of extracellular vesicles by salivary glands and ovary cells

“…EVs were isolated from tick hemolymph by differential centrifugation, as previously described [ 48 ]. The hemolymph was mixed with an equal volume of PBS and centrifuged at 500 × g for 10 min at 4 °C to remove any contaminating cells.…”

“…The 4D label-free proteomic protocol used here was described previously in [ 48 , 49 ]. Briefly, SDT (4% SDS, 100 mM Tris–HCl, 1 mM DTT, pH 7.6) buffer was used for sample lysis and protein extraction.…”