Pathogenesis Of Diabetic Peripheral Neuropathy Research Articles

Exploring the role of mitochondrial-associated and peripheral neuropathy genes in the pathogenesis of diabetic peripheral neuropathy

BackgroundDiabetic peripheral neuropathy (DPN) is a prevalent and serious complication of diabetes mellitus, impacting the nerves in the limbs and leading to symptoms like pain, numbness, and diminished function. While the exact molecular and immune mechanisms underlying DPN remain incompletely understood, recent findings indicate that mitochondrial dysfunction may play a role in the advancement of this diabetic condition.MethodsTwo RNA transcriptome datasets (codes: GSE185011 and GSE95849), comprising samples from diabetic peripheral neuropathy (DPN) patients and healthy controls (HC), were retrieved from the Gene Expression Omnibus (GEO) database hosted by the National Center for Biotechnology Information (NCBI). Subsequently, differential expression analysis and gene set enrichment analysis were performed. Protein–protein interaction (PPI) networks were constructed to pinpoint key hub genes associated with DPN, with a specific emphasis on genes related to mitochondria and peripheral neuropathy disease (PND) that displayed differential expression. Additionally, the study estimated the levels of immune cell infiltration in both the HC and DPN samples. To validate the findings, quantitative polymerase chain reaction (qPCR) was employed to confirm the differential expression of selected genes in the DPN samples.ResultsThis research identifies four hub genes associated mitochondria or PN. Furthermore, the analysis revealed increased immune cell infiltration in DPN tissues, particularly notable for macrophages and T cells. Additionally, our investigation identified potential drug candidates capable of regulating the expression of the four hub genes. These findings were corroborated by qPCR results, reinforcing the credibility of our bioinformatics analysis.ConclusionsThis study provides a comprehensive overview of the molecular and immunological characteristics of DPN, based on both bioinformatics and experimental methods.

VGLUT2 and APP family: unraveling the neurobiochemical mechanisms of neurostimulation therapy to STZ-induced diabetes and neuropathy.

Diabetic Peripheral Neuropathy (DPN) poses an escalating threat to public health, profoundly impacting well-being and quality of life. Despite its rising prevalence, the pathogenesis of DPN remains enigmatic, and existing clinical interventions fall short of achieving meaningful reversals of the condition. Notably, neurostimulation techniques have shown promising efficacy in alleviating DPN symptoms, underscoring the imperative to elucidate the neurobiochemical mechanisms underlying DPN. This study employs an integrated multi-omics approach to explore DPN and its response to neurostimulation therapy. Our investigation unveiled a distinctive pattern of vesicular glutamate transporter 2 (VGLUT2) expression in DPN, rigorously confirmed through qPCR and Western blot analyses in DPN C57 mouse model induced by intraperitoneal Streptozotocin (STZ) injection. Additionally, combining microarray and qPCR methodologies, we revealed and substantiated variations in the expression of the Amyloid Precursor Protein (APP) family in STZ-induced DPN mice. Analyzing the transcriptomic dataset generated from neurostimulation therapy for DPN, we intricately explored the differential expression patterns of VGLUT2 and APPs. Through correlation analysis, protein-protein interaction predictions, and functional enrichment analyses, we predicted the key biological processes involving VGLUT2 and the APP family in the pathogenesis of DPN and during neurostimulation therapy. This comprehensive study not only advances our understanding of the pathogenesis of DPN but also provides a theoretical foundation for innovative strategies in neurostimulation therapy for DPN. The integration of multi-omics data facilitates a holistic view of the molecular intricacies of DPN, paving the way for more targeted and effective therapeutic interventions.

Novel drugs affecting diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) poses a significant threat, affecting half of the global diabetic population and leading to severe complications, including pain, impaired mobility, and potential amputation. The delayed manifestation of diabetic neuropathy (DN) makes early diagnosis challenging, contributing to its debilitating impact on individuals with diabetes mellitus (DM). This review examines the multifaceted nature of DPN, focusing on the intricate interplay between oxidative stress, metabolic pathways, and the resulting neuronal damage. It delves into the challenges of diagnosing DN, emphasizing the critical role played by hyperglycemia in triggering these cascading effects. Furthermore, the study explores the limitations of current neuropathic pain drugs, prompting an investigation into a myriad of pharmaceutical agents tested in both human and animal trials over the past decade. The methodology scrutinizes these agents for their potential to provide symptomatic relief for DPN. The investigation reveals promising results from various pharmaceutical agents tested for DPN relief, showcasing their efficacy in ameliorating symptoms. However, a notable gap persists in addressing the underlying problem of DPN. The results underscore the complexity of DPN and the challenges in developing therapies that go beyond symptomatic relief. Despite advancements in treating DPN symptoms, there remains a scarcity of options addressing the underlying problem. This review consolidates the state-of-the-art drugs designed to combat DPN, highlighting their efficacy in alleviating symptoms. Additionally, it emphasizes the need for a deeper understanding of the diverse processes and pathways involved in DPN pathogenesis.

Unraveling the Role of Tumor Necrosis Factor-Alpha in Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes mellitus, leading to sensory abnormalities, decreased balance, and increased risk of foot problems. Although tumor necrosis factor-alpha (TNF-α) has emerged as a potential factor in the pathogenesis of DPN, its role remains contested. This study intends to thoroughly analyze the association between TNF-α and DPN by combining data from various global studies. This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and included 23 articles investigating TNF-α levels in DPN patients for systematic review and 11 articles for meta-analysis. Data were extracted, and heterogeneity was examined. A random-effect model was chosen due to high heterogeneity. The major outcome measure across studies was serum TNF-α levels. The meta-analysis found a significant mean difference of 15.2464 (95% confidence interval = 4.4963; 25.9965) under the random-effect model due to the substantial heterogeneity (I2 = 98.1%) among included studies. The meta-analysis indicates a consistent elevation in TNF-α levels in individuals with DPN compared to those without neuropathy. This underlines the potential of TNF-α as a biomarker and contributor to diabetic neuropathy. Despite heterogeneity, the study's extensive scope and systematic approach enhance the trustworthiness and generalizability of the findings.

Diagnostic biomarker for type 2 diabetic peripheral neuropathy via comprehensive bioinformatics analysis.

Diabetic peripheral neuropathy (DPN) is a common complication of Type 2 diabetes mellitus (T2DM), which frequently results in disabling neuropathic pain and lower-limb amputation. The identification of noninvasive biomarkers for DPN may help early detection and individualized treatment of DPN. In this study, we identified differentially expressed genes (DEGs) between DPN and the control based on blood-source (GSE95849) and tissue-source gene expression profiles (GSE143979) from the Gene Expression Omnibus (GEO) database using limma, edgeR, and DESeq2 approaches. KEGGG and GO functional enrichments were performed. Hub genes and their correlation with infiltrating immune cells were analyzed. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to quantify hub gene expression. In total, 144 DEGs between DPN and the control were identified. Functional enrichment revealed that the DEGs were mainly enriched in immune-related pathways like the Fc epsilon receptor Ig signaling pathway. By protein-protein interaction (PPI) network analysis, FCER1G, SYK, ITGA4, F13A1, MS4A2, and PTK2B were screened as hub genes with higher expression in DPN patients, among which half were immune genes (FCER1G, PTK2B, and SYK). RT-qPCR demonstrated that mRNA expression of FCER1G, PTK2B, and SYK was significantly increased in patients with DPN compared with both diabetic nonperipheral neuropathy (DNN) and normal subjects. The area under the receiver operating characteristic (ROC) curve of FCER1G, PTK2B, and SYK was 0.84, 0.81, and 0.73, respectively, suggesting their great advantages as diagnostic biomarkers to predict the progression of neuropathy in T2DM. Further analysis indicated that the expression of FCER1G, PTK2B, and SYK was negatively correlated with the cell proportion of significantly altered resting natural killer cells, T follicular helper cells, and activated mast cells, but positively correlated with monocytes. Our findings demonstrated FCER1G, PTK2B, and SYK are potential diagnostic biomarkers and therapeutic targets for DPN, which provides new insight into DPN pathogenesis and therapies.

Targeted metabolomics reveals the aberrant energy status in diabetic peripheral neuropathy and the neuroprotective mechanism of traditional Chinese medicine JinMaiTong

Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, for which effective therapies are currently lacking. Disturbed energy status plays a crucial role in DPN pathogenesis. However, the integrated profile of energy metabolism, especially the central carbohydrate metabolism, remains unclear in DPN. Here, we developed a metabolomics approach by targeting 56 metabolites using high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) to illustrate the integrative characteristics of central carbohydrate metabolism in patients with DPN and streptozotocin-induced DPN rats. Furthermore, JinMaiTong (JMT), a traditional Chinese medicine (TCM) formula, was found to be effective for DPN, improving the peripheral neurological function and alleviating the neuropathology of DPN rats even after demyelination and axonal degeneration. JMT ameliorated DPN by regulating the aberrant energy balance and mitochondrial functions, including excessive glycolysis restoration, tricarboxylic acid cycle improvement, and increased adenosine triphosphate (ATP) generation. Bioenergetic profile was aberrant in cultured rat Schwann cells under high-glucose conditions, which was remarkably corrected by JMT treatment. In-vivo and in-vitro studies revealed that these effects of JMT were mainly attributed to the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and downstream peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our results expand the therapeutic framework for DPN and suggest the integrative modulation of energy metabolism using TCMs, such as JMT, as an effective strategy for its treatment.

Urinary acrolein protein conjugates-to-creatinine ratio is positively associated with diabetic peripheral neuropathy in patients with type 2 diabetes mellitus.

Acrolein, an unsaturated aldehyde, plays a pathological role in neurodegenerative diseases. However, less is known about its effects on peripheral neuropathy. The aim of this study was to investigate the association of acrolein and diabetic peripheral neuropathy in patients with type 2 diabetes. We recruited 148 ambulatory patients with type 2 diabetes. Each participant underwent an assessment of the Michigan Neuropathy Screening Instrument Physical Examination. Diabetic peripheral neuropathy was defined as Michigan Neuropathy Screening Instrument Physical Examination score ≥ 2.5. Serum levels and urinary levels of acrolein protein conjugates were measured. Urinary acrolein protein conjugates-to-creatinine ratios were determined. Patients with diabetic peripheral neuropathy had significantly higher urinary acrolein protein conjugates-to-creatinine ratios than those without diabetic peripheral neuropathy (7.91, 95% CI: 5.96-10.50 vs 5.31, 95% CI: 4.21-6.68, P = 0.029). Logarithmic transformation of urinary acrolein protein conjugates-to-creatinine ratios was positively associated with diabetic peripheral neuropathy in univariate logistic analysis, and the association remained significant in multivariate analysis (OR = 2.45, 95% CI: 1.12-5.34, P = 0.025). In conclusion, urinary acrolein protein conjugates-to-creatinine ratio may act as a new biomarker for diabetic peripheral neuropathy in type 2 diabetes. The involvement of acrolein in the pathogenesis of diabetic peripheral neuropathy warrants further investigation.

Three genes expressed in relation to lipid metabolism considered as potential biomarkers for the diagnosis and treatment of diabetic peripheral neuropathy

Diabetic neuropathy is one of the most common chronic complications and is present in approximately 50% of diabetic patients. A bioinformatic approach was used to analyze candidate genes involved in diabetic distal symmetric polyneuropathy and their potential mechanisms. GSE95849 was downloaded from the Gene Expression Omnibus database for differential analysis, together with the identified diabetic peripheral neuropathy-associated genes and the three major metabolism-associated genes in the CTD database to obtain overlapping Differentially Expressed Genes (DEGs). Gene Set Enrichment Analysis and Functional Enrichment Analysis were performed. Protein–Protein Interaction and hub gene networks were constructed using the STRING database and Cytoscape software. The expression levels of target genes were evaluated using GSE24290 samples, followed by Receiver operating characteristic, curve analysis. And Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the target genes. Finally, mRNA-miRNA networks were constructed. A total of 442 co-expressed DEGs were obtained through differential analysis, of which 353 expressed up-regulated genes and 89 expressed down-regulated genes. The up-regulated DEGs were involved in 742 GOs and 10 KEGG enrichment results, mainly associated with lipid metabolism-related pathways, TGF-β receptor signaling pathway, lipid transport, and PPAR signaling pathway. A total of 4 target genes (CREBBP, EP300, ME1, CD36) were identified. Analysis of subject operating characteristic curves indicated that CREBBP (AUC = 1), EP300 (AUC = 0.917), ME1 (AUC = 0.944) and CD36 (AUC = 1) may be candidate serum biomarkers for DPN. Conclusion: Diabetic peripheral neuropathy pathogenesis and progression is caused by multiple pathways, which also provides clinicians with potential therapeutic tools.

Bioinformatics analysis identifies potential ferroptosis key genes in the pathogenesis of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a serious complication in Diabetes Mellitus (DM) patients and the underlying mechanism is yet unclear. Ferroptosis has been recently intensively researched as a key process in the pathogenesis of diabetes but there yet has been no related bioinformatics-based studies in the context of DPN. We used data mining and data analysis techniques to screen differentially expressed genes (DEGs) and immune cell content in patients with DPN, DM patients and healthy participants (dataset GSE95849). These DEGs were then intersected with the ferroptosis dataset (FerrDb) to obtain ferroptosis DEGs and the associated key molecules and miRNAs interactions were predicted. A total of 33 ferroptosis DEGs were obtained. Functional pathway enrichment analysis revealed 127 significantly related biological processes, 10 cellular components, 3 molecular functions and 30 KEGG signal pathways. The biological processes that were significantly enriched were in response to extracellular stimulus and oxidative stress. Key modules constructed by the protein-protein interaction network analysis led to the confirmation of the following genes of interest: DCAF7, GABARAPL1, ACSL4, SESN2 and RB1. Further miRNA interaction prediction revealed the possible involvement of miRNAs such as miR108b-8p, miR34a-5p, mir15b-5p, miR-5838-5p, miR-192-5p, miR-222-3p and miR-23c. Immune-environment content of samples between DM and DPN patients revealed significant difference in the levels of endothelial cells and fibroblasts, which further speculates their possible involvement in the pathogenesis of DPN. Our findings could provide insight for investigations about the role of ferroptosis in the development of DPN.

Oxidative Stress in Diabetic Peripheral Neuropathy: Pathway and Mechanism-Based Treatment.

Diabetic peripheral neuropathy (DPN) is a major complication of diabetes mellitus with a high incidence. Oxidative stress, which is a crucial pathophysiological pathway of DPN, has attracted much attention. The distortion in the redox balance due to the overproduction of reactive oxygen species (ROS) and the deregulation of antioxidant defense systems promotes oxidative damage in DPN. Therefore, we have focused on the role of oxidative stress in the pathogenesis of DPN and elucidated its interaction with other physiological pathways, such as the glycolytic pathway, polyol pathway, advanced glycosylation end products, protein kinase C pathway, inflammation, and non-coding RNAs. These interactions provide novel therapeutic options targeting oxidative stress for DPN. Furthermore, our review addresses the latest therapeutic strategies targeting oxidative stress for the rehabilitation of DPN. Antioxidant supplements and exercise have been proposed as fundamental therapeutic strategies for diabetic patients through ROS-mediated mechanisms. In addition, several novel drug delivery systems can improve the bioavailability of antioxidants and the efficacy of DPN.

Axonal transport deficits in the pathogenesis of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a chronic and prevalent metabolic disease that gravely endangers human health and seriously affects the quality of life of hyperglycemic patients. More seriously, it can lead to amputation and neuropathic pain, imposing a severe financial burden on patients and the healthcare system. Even with strict glycemic control or pancreas transplantation, peripheral nerve damage is difficult to reverse. Most current treatment options for DPN can only treat the symptoms but not the underlying mechanism. Patients with long-term diabetes mellitus (DM) develop axonal transport dysfunction, which could be an important factor in causing or exacerbating DPN. This review explores the underlying mechanisms that may be related to axonal transport impairment and cytoskeletal changes caused by DM, and the relevance of the latter with the occurrence and progression of DPN, including nerve fiber loss, diminished nerve conduction velocity, and impaired nerve regeneration, and also predicts possible therapeutic strategies. Understanding the mechanisms of diabetic neuronal injury is essential to prevent the deterioration of DPN and to develop new therapeutic strategies. Timely and effective improvement of axonal transport impairment is particularly critical for the treatment of peripheral neuropathies.

Mechanism of Schwann cells in diabetic peripheral neuropathy: A review.

Diabetic peripheral neuropathy (DPN) is the most common neuropathy in the world, mainly manifested as bilateral symmetry numbness, pain or paresthesia, with a high rate of disability and mortality. Schwann cells (SCs), derived from neural ridge cells, are the largest number of glial cells in the peripheral nervous system, and play an important role in DPN. Studies have found that SCs are closely related to the pathogenesis of DPN, such as oxidative stress, endoplasmic reticulum stress, inflammation, impaired neurotrophic support and dyslipidemia. This article reviews the mechanism of SCs in DPN.

Identification of Immune Infiltration and the Potential Biomarkers in Diabetic Peripheral Neuropathy through Bioinformatics and Machine Learning Methods.

Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications in diabetes. Previous studies have shown that chronic neuroinflammation was associated with DPN. However, further research is needed to investigate the exact immune molecular mechanism underlying the pathogenesis of DPN. Expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened by R software. After functional enrichment analysis of DEGs, a protein-protein interaction (PPI) network analysis was performed. The CIBERSORT algorithm was used to evaluate the infiltration of immune cells in DPN. Next, the least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were applied to identify potential DPN diagnostic markers. Finally, the results were further validated by qRT-PCR. A total of 1308 DEGs were screened in this study. Enrichment analysis identified that DEGs were significantly enriched in immune-related biological functions and pathways. Immune cell infiltration analysis found that M1 and M2 macrophages, monocytes, resting mast cells, resting CD4 memory T cells and follicular helper T cells were involved in the development of DPN. LTBP2 and GPNMB were identified as diagnostic markers of DPN. qRT-PCR results showed that 15 mRNAs, including LTBP2 and GPNMB, were differentially expressed, consistent with the microarray results. In conclusion, LTBP2 and GPNMB can be used as novel candidate molecular diagnostic markers for DPN. Furthermore, the infiltration of immune cells plays an important role in the progression of DPN.

Schwann cells-derived exosomal miR-21 participates in high glucose regulation of neurite outgrowth

SummaryAs a common complication of diabetes, the pathogenesis of diabetic peripheral neuropathy (DPN) is closely related to high glucose but has not been clarified. Exosomes can mediate crosstalk between Schwann cells (SC) and neurons in the peripheral nerve. Herein, we found that miR-21 in serum exosomes from DPN rats was decreased. SC proliferation was inhibited, cell apoptosis was increased, and the expression of miR-21 in cells and exosomes was downregulated when cultured in high glucose. Increasing miR-21 expression reversed these changes, while knockdown of miR-21 led to the opposite results. When co-cultured with exosomes derived from SC exposed to high glucose, neurite outgrowth was inhibited. On the contrary, neurite outgrowth was accelerated when incubated with exosomes rich in miR-21. We further demonstrated that the SC-derived exosomal miR-21 participates in neurite outgrowth probably through the AKT signaling pathway. Thus, SC-derived exosomal miR-21 contributes to high glucose regulation of neurite outgrowth.

Melatonin receptor gene polymorphisms as a risk factor in patients with diabetic peripheral neuropathy.

Oxidative stress plays an important role in the pathogenesis of diabetic peripheral neuropathy (DPN). Melatonin is one of the most powerful endogenous antioxidants and has anti-inflammatory properties. We investigated how the gene polymorphism of melatonin differs in patients with DPN compared to an healthy control group. A total of 54 diabetic peripheral neuropathy patients who applied to the Neurology outpatient clinic between 2020 and 2021, and 53 healthy controls comparable with the patient group in terms of age and gender were included in the study. Electromyography was performed and the melatonin gene polymorphism was analysed using the pyrosequencing method. Melatonin gene variants rs2119882, rs13140012, and rs10830963 were analysed in patients and controls. The rs2119882 (G allele) has a protective role, and rs13140012 polymorphism has a related 5-fold higher risk of DPN in the recessive model. Melatonin gene polymorphisms have been shown to be associated with DPN. This is the first and only study investigating the relationship between melatonin gene polymorphisms and DPN. Ethnicity is very important in genetic studies, and it will give us more information on the role of melatonin gene variantsin larger study groups of diabeticpatients of other ethnic origin.

Shared and specific biological signalling pathways for diabetic retinopathy, peripheral neuropathy and nephropathy by high-throughput sequencing analysis.

ObjectivesWe aimed to explore the shared and specific signalling pathways involved in diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN).MethodsDifferentially expressed mRNAs and lncRNAs were identified by high-throughput sequencing. Subsequently, functional enrichment analysis, protein-protein interaction (PPI) analysis and lncRNAs-mRNAs networks were conducted to determine the pathogenic mechanisms underlying DR, DPN and DN.ResultsTwenty-six biological pathways were shared among DR, DPN and DN groups compared to the type 2 diabetes mellitus (T2DM) group without complications, and most of the shared pathways and core proteins were involved in immune and inflammatory responses of microvascular damage. Cytokine‒cytokine receptor interactions and chemokine signalling pathway were the most significant and specific pathways for DR, and the lncRNA‒mRNA regulatory networks affected DR by targeting these pathways. Sphingolipid metabolism and neuroactive ligand-receptor pathways were found to be specific for the pathogenesis of DPN. Moreover, multiple amino acid metabolic pathways were involved in the occurrence and progression of DN.ConclusionsDiabetic retinopathy, DPN and DN exhibited commonality and heterogeneity simultaneously. The shared pathologic mechanisms underlying these diabetic complications are involved in diabetic microvascular damage via immune and inflammatory pathways. Our findings predict several biomarkers and therapeutic targets for these diabetic complications.

MicroRNA-7a-5p ameliorates diabetic peripheral neuropathy by regulating VDAC1/JNK/c-JUN pathway.

The pathogenesis of diabetic peripheral neuropathy (DPN) is complex, and its treatment is extremely challenging. MicroRNA-7a-5p (miR-7a-5p) has been widely reported to alleviate apoptosis and oxidative stress in various diseases. This study aimed to investigate the mechanism of miR-7a-5p in DPN. DPN cell model was constructed with high-glucose-induced RSC96 cells. Cell apoptosis and viability were detected by flow cytometry analysis and cell counting kit-8 (CCK-8) assay respectively. The apoptosis and Jun N-terminal kinase (JNK)/c-JUN signalling pathway-related proteins expression were detected by Western blotting. The intracellular calcium content and oxidative stress levels were detected by flow cytometry and reagent kits. Mitochondrial membrane potential was evaluated by tetrechloro-tetraethylbenzimidazol carbocyanine iodide (JC-1) staining. The targeting relationship between miR-7a-5p and voltage-dependent anion-selective channel protein 1 (VDAC1) was determined by RNA pull-down assay and dual-luciferase reporter gene assay. The streptozotocin (STZ) rat model was constructed to simulate DPN in vivo. The paw withdrawal mechanical threshold (PTW) was measured by Frey capillary line, and the motor nerve conduction velocity (MNCV) was measured by electromyography. MiR-7a-5p expression was decreased, while VDAC1 expression was increased in HG-induced RSC96 cells and STZ rats. In HG-induced RSC96 cells, miR-7a-5p overexpression promoted cell proliferation, inhibited apoptosis, down-regulated calcium release, improved mitochondrial membrane potential and repressed oxidative stress response. MiR-7a-5p negatively regulated VDAC1 expression. VDAC1 knockdown improved cell proliferation activity, suppressed cell apoptosis and mitochondrial dysfunction by inhibiting JNK/c-JUN pathway activation. MiR-7a-5p overexpression raised PTW, restored MNCV and reduced oxidative stress levels and nerve cell apoptosis in STZ rats. MiR-7a-5p overexpression ameliorated mitochondrial dysfunction and inhibited apoptosis in DPN by regulating VDAC1/JNK/c-JUN pathway.

Sphingolipid metabolism plays a key role in diabetic peripheral neuropathy.

As the most common chronic complication of diabetes mellitus (DM), diabetic peripheral neuropathy (DPN) seriously affects the quality of life of DM patients. So, it is of great significance for the diagnosis and treatment of DPN. In recent years, there have been numerous studies on pathogenesis and biomarkers of DM, but there are few studies on the biomarkers of DPN. This research is intended to identify abnormal metabolic pathways, search for potential biomarkers of DPN, and provide a metabolic basis for the diagnosis and mechanism of DPN. Serum samples from 23 healthy controls (HC), 42 DM patients and 30 DPN patients and urine samples from 42 HC, 40 DM patients, and 30 DPN patients were collected. UPLC-Q-TOF/MS was used to analyze the samples. Potential biomarkers were screened from principal component analysis (PCA) to orthogonal partial least squares discriminant analysis (OPLS-DA) and further evaluated by receiver operating characteristic analysis (ROC). The biomarkers were then enriched and pathway analyzed. 12 potential DPN biomarkers were identified from patient's serum. 11 potential DPN biomarkers were identified from the patient's urine. Among them, the diagnostic ability of gluconic acid, lipoic acid, sphinganine, bilirubin, sphingosine and 4-hydroxybenzoic acid was increased by ROC analysis. Potential biomarkers suggest that the disorder of DPN metabolism may be linked to sphingolipid metabolism. This research laid a theoretical foundation for the diagnosis and pathogenesis of DPN.

Activation of 20-HETE Synthase Triggers Oxidative Injury and Peripheral Nerve Damage in Type 2 Diabetic Mice

Diabetic Peripheral Neuropathy (DPN), highly prevalent among patients with diabetes, is characterized by peripheral nerve dysfunction. Reactive Oxygen Species (ROS) overproduction has been suggested to orchestrate diabetic complications including DPN. Untargeted antioxidant therapy has exhibited limited efficacy, highlighting a critical need to explore ROS sources altered in a cell-specific manner in DPN. Cytochromes P450 (CYP) enzymes are prominent sources of ROS. Particularly, the 20-HETE synthase, CYP4A, is reported to mediate diabetes-induced renal, retinal, and cardiovascular injuries. This work investigates the role of CYP4A/20-HETE in DPN and their mechanisms of action. Non-obese type 2 Diabetic mice (MKR) were used and treated with a CYP4A-inhibitor (HET0016) or AMPK-activator (Metformin). Peripheral nerves of MKR mice reflect increased CYP4A and 20-HETE levels, concurrent with altered myelin proteins and sensorimotor deficits. This was associated with increased ROS production and altered Beclin-1 and LC3 protein levels, indicative of disrupted autophagic responses in tandem with AMPK inactivation. AMPK activation via Metformin restored nerve integrity, reduced ROS production, and regulated autophagy. Interestingly, similar outcomes were revealed upon HET0016 treatment whereby ROS production, autophagic responses, and AMPK signaling were normalized in diabetic mice. Altogether, the results highlight hyperglycemia-mediated oxidative injury in DPN through a novel CYP4A/20-HETE/AMPK pathological axis. PerspectiveTo our knowledge, this is the first study to highlight the role of CYPs/20-HETE-induced oxidative injury in the pathogenesis of diabetic peripheral neuropathy. Targeting the identified pathological axis CYP4A/20-HETE/AMPK may be of clinical potential in predicting and alleviating peripheral nerve injury in patients with Type 2 Diabetes Mellitus.

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

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.