{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:03:55Z","timestamp":1780376635353,"version":"3.54.1"},"reference-count":122,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Diabetic peripheral neuropathy (DPN) remains a leading cause of disability in diabetes, yet current care is largely symptomatic and does not directly address early neurovascular-immune pathology. This narrative review synthesizes clinical, redox, vascular, and immunological evidence into a peripheral nerve neurovascular unit (PNVU)\/blood\u2013nerve barrier (BNB)-centered framework for DPN. First, the review outlines the diagnostic and translational endpoint landscape of DPN, emphasizing that commonly used clinical, neurophysiological, small-fiber, and imaging-based tools capture important disease domains but do not directly assess early BNB dysfunction. It then reviews the anatomical and functional basis of the PNVU and BNB, including endoneurial microvascular endothelial cells, pericytes, basement membrane components, immune cells, and tight-junction proteins. Next, it discusses how chronic hyperglycemia and dyslipidemia drive metabolic-to-vascular coupling, redox imbalance, antioxidant defense failure, advanced glycation end products (AGEs), receptor for AGEs (RAGE), and nuclear factor-\u03baB (NF-\u03baB) signaling, endothelial activation, leukocyte recruitment, macrophage polarization, and junctional disassembly, culminating in increased BNB permeability and exposure of peripheral nerves to pro-inflammatory and neurotoxic mediators. Finally, it evaluates incretin-based therapies\u2014including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors, DPP-4is), and emerging multi-agonists\u2014as potential modulators of oxidative and inflammatory stress within this framework. Although semaglutide and related agents show mechanistic plausibility and preclinical promise, direct evidence for incretin-mediated BNB stabilization in human DPN remains limited. By reframing DPN as a redox-driven neurovascular-immune disorder, this review highlights barrier-focused biomarkers, translational endpoints, and hypothesis-generating therapeutic opportunities that require clinical validation.<\/jats:p>","DOI":"10.3390\/antiox15060670","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T16:17:58Z","timestamp":1779812278000},"page":"670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Redox-Driven Blood\u2013Nerve Barrier Dysfunction in Diabetic Peripheral Neuropathy: Mechanisms and Therapeutic Opportunities"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3842-8320","authenticated-orcid":false,"given":"Wei-Hsiu","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Cathay General Hospital, Taipei 106, Taiwan"},{"name":"Graduate Institute of Medical Sciences, National Defense Medical University, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-9950","authenticated-orcid":false,"given":"Chih-Shung","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Cathay General Hospital, Taipei 106, Taiwan"},{"name":"Graduate Institute of Medical Sciences, National Defense Medical University, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0140-6736(23)01301-6","article-title":"Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021","volume":"402","author":"Ong","year":"2023","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/S1474-4422(22)00188-0","article-title":"Towards prevention of diabetic peripheral neuropathy: Clinical presentation, pathogenesis, and new treatments","volume":"21","author":"Elafros","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41572-019-0092-1","article-title":"Diabetic neuropathy","volume":"5","author":"Feldman","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.pcd.2019.12.005","article-title":"Prevalence of peripheral neuropathy in patients with diabetes: A systematic review and meta-analysis","volume":"14","author":"Sun","year":"2020","journal-title":"Prim. Care Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zhou, P., Zhou, J.S., Li, J.J., Qin, L., Hu, W.F., Zhang, X.Y., Wang, J.X., and Shi, Z. (2025). Prevalence and risk factors for painful diabetic peripheral neuropathy: A systematic review and meta-analysis. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1564867"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41574-022-00690-7","article-title":"The burden and risks of emerging complications of diabetes mellitus","volume":"18","author":"Tomic","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"255","DOI":"10.4093\/dmj.2018.0056","article-title":"Diagnosing Diabetic Neuropathy: Something Old, Something New","volume":"42","author":"Petropoulos","year":"2018","journal-title":"Diabetes Metab. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/S2213-8587(19)30081-6","article-title":"Diabetic peripheral neuropathy: Advances in diagnosis and strategies for screening and early intervention","volume":"7","author":"Selvarajah","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhu, J., Hu, Z., Luo, Y., Liu, Y., Luo, W., Du, X., Luo, Z., Hu, J., and Peng, S. (2024). Diabetic peripheral neuropathy: Pathogenetic mechanisms and treatment. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1265372"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Khalid, M., Petroianu, G., and Adem, A. (2022). Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives. Biomolecules, 12.","DOI":"10.3390\/biom12040542"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1007\/s12035-023-03342-7","article-title":"Oxidative Stress in Diabetic Peripheral Neuropathy: Pathway and Mechanism-Based Treatment","volume":"60","author":"Lin","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rusli, N., Ng, C.F., Makpol, S., Wong, Y.P., Mohd Isa, I.L., and Remli, R. (2024). Antioxidant Effect in Diabetic Peripheral Neuropathy in Rat Model: A Systematic Review. Antioxidants, 13.","DOI":"10.3390\/antiox13091041"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.phrs.2015.09.014","article-title":"Heme oxygenase-1, a novel target for the treatment of diabetic complications: Focus on diabetic peripheral neuropathy","volume":"102","author":"Negi","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e184075","DOI":"10.1172\/JCI184075","article-title":"Cell and molecular profiles in peripheral nerves shift toward inflammatory phenotypes in diabetic peripheral neuropathy","volume":"135","author":"Shen","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Richner, M., Ferreira, N., Dudele, A., Jensen, T.S., Vaegter, C.B., and Gon\u00e7alves, N.P. (2018). Functional and Structural Changes of the Blood-Nerve-Barrier in Diabetic Neuropathy. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.01038"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wu, P.-z., Yao, J., Meng, B., Qin, Y.-B., and Cao, S. (2023). Blood-nerve barrier enhances chronic postsurgical pain via the HIF-1\u03b1\/aquaporin-1 signaling axis. BMC Anesthesiol., 23.","DOI":"10.1186\/s12871-023-02306-7"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Takeshita, Y., Sato, R., and Kanda, T. (2020). Blood-Nerve Barrier (BNB) Pathology in Diabetic Peripheral Neuropathy and In Vitro Human BNB Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010062"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.devcel.2023.01.002","article-title":"Characterization of the structure and control of the blood-nerve barrier identifies avenues for therapeutic delivery","volume":"58","author":"Malong","year":"2023","journal-title":"Dev. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Siddiqui, K., George, T.P., Mujammami, M., Isnani, A., and Alfadda, A.A. (2023). The association of cell adhesion molecules and selectins (VCAM-1, ICAM-1, E-selectin, L-selectin, and P-selectin) with microvascular complications in patients with type 2 diabetes: A follow-up study. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1072288"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.4239\/wjd.v14.i7.1013","article-title":"Tight junction disruption and the pathogenesis of the chronic complications of diabetes mellitus: A narrative review","volume":"14","author":"Sabath","year":"2023","journal-title":"World J. Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Reinhold, A.K., Schwabe, J., Lux, T.J., Salvador, E., and Rittner, H.L. (2018). Quantitative and Microstructural Changes of the Blood-Nerve Barrier in Peripheral Neuropathy. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00936"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1007\/s00125-011-2107-7","article-title":"Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood\u2013nerve barrier by stimulating the release of TGF-\u03b2 and vascular endothelial growth factor (VEGF) by pericytes","volume":"54","author":"Shimizu","year":"2011","journal-title":"Diabetologia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2042018821997320","DOI":"10.1177\/2042018821997320","article-title":"GLP-1 receptor agonists: An updated review of head-to-head clinical studies","volume":"12","author":"Trujillo","year":"2021","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(21)00213-0","article-title":"Semaglutide 2\u00b74 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial","volume":"397","author":"Davies","year":"2021","journal-title":"Lancet"},{"key":"ref_25","first-page":"891","article-title":"Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","volume":"376","author":"Marso","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Patti, A.M., Giglio, R.V., Allotta, A., Bruno, A., Di Bella, T., Pantea Stoian, A., Ciaccio, M., and Rizzo, M. (2023). Effect of Semaglutide on Subclinical Atherosclerosis and Cardiometabolic Compensation: A Real-World Study in Patients with Type 2 Diabetes. Biomedicines, 11.","DOI":"10.3390\/biomedicines11051362"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/dom.14863","article-title":"Semaglutide for the treatment of overweight and obesity: A review","volume":"25","author":"Bergmann","year":"2023","journal-title":"Diabetes Obes. Metab."},{"key":"ref_28","first-page":"6813017","article-title":"Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress","volume":"2022","author":"Liu","year":"2022","journal-title":"Park. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kalinderi, K., Papaliagkas, V., and Fidani, L. (2024). GLP-1 Receptor Agonists: A New Treatment in Parkinson\u2019s Disease. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202402.1245.v1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1177\/0271678X20952011","article-title":"Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: A systematic scoping review","volume":"41","author":"Maskery","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"107748","DOI":"10.1016\/j.neuropharm.2019.107748","article-title":"The diabetes drug semaglutide reduces infarct size, inflammation, and apoptosis, and normalizes neurogenesis in a rat model of stroke","volume":"158","author":"Yang","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13825","DOI":"10.1038\/s41598-022-17338-1","article-title":"A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease","volume":"12","author":"Hughes","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13098-024-01528-0","article-title":"Semaglutide restores astrocyte-vascular interactions and blood-brain barrier integrity in a model of diet-induced metabolic syndrome","volume":"17","author":"Estato","year":"2025","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.62347\/IZGJ1332","article-title":"Semaglutide alleviates early brain injury following subarachnoid hemorrhage by suppressing ferroptosis and neuroinflammation via SIRT1 pathway","volume":"16","author":"Chen","year":"2024","journal-title":"Am. J. Transl. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.jocn.2020.09.054","article-title":"Semaglutide-mediated protection against A\u03b2 correlated with enhancement of autophagy and inhibition of apotosis","volume":"81","author":"Chang","year":"2020","journal-title":"J. Clin. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lee, S.O., Kuthati, Y., Huang, W.H., and Wong, C.S. (2024). Semaglutide Ameliorates Diabetic Neuropathic Pain by Inhibiting Neuroinflammation in the Spinal Cord. Cells, 13.","DOI":"10.3390\/cells13221857"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2337\/dc16-2042","article-title":"Diabetic Neuropathy: A Position Statement by the American Diabetes Association","volume":"40","author":"Boulton","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2025). 12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2025. Diabetes Care, 48, S252\u2013S265.","DOI":"10.2337\/dc25-S012"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.2337\/dc10-1303","article-title":"Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments","volume":"33","author":"Tesfaye","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"903-e49","DOI":"10.1111\/j.1468-1331.2010.03023.x","article-title":"European Federation of Neurological Societies\/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society","volume":"17","author":"Lauria","year":"2010","journal-title":"Eur. J. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1177\/193229681300700509","article-title":"Corneal confocal microscopy to assess diabetic neuropathy: An eye on the foot","volume":"7","author":"Tavakoli","year":"2013","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Selvarajah, D., Cash, T., Davies, J., Sankar, A., Rao, G., Grieg, M., Pallai, S., Gandhi, R., Wilkinson, I.D., and Tesfaye, S. (2015). SUDOSCAN: A Simple, Rapid, and Objective Method with Potential for Screening for Diabetic Peripheral Neuropathy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138224"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.pain.2006.01.041","article-title":"Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values","volume":"123","author":"Rolke","year":"2006","journal-title":"PAIN\u00ae"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1097\/j.pain.0000000000000433","article-title":"Quantitative sensory testing using DFNS protocol in Europe: An evaluation of heterogeneity across multiple centers in patients with peripheral neuropathic pain and healthy subjects","volume":"157","author":"Vollert","year":"2016","journal-title":"PAIN\u00ae"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.pmrj.2008.11.011","article-title":"Practice Parameter: The Evaluation of Distal Symmetric Polyneuropathy: The Role of Autonomic Testing, Nerve Biopsy, and Skin Biopsy (An Evidence-Based Review): Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation","volume":"1","author":"England","year":"2009","journal-title":"PM&R"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1111\/j.1464-5491.2009.02667.x","article-title":"Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy","volume":"26","author":"Bril","year":"2009","journal-title":"Diabet. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.2337\/diacare.25.11.2048","article-title":"Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy","volume":"25","author":"Bril","year":"2002","journal-title":"Diabetes Care"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.pain.2004.12.010","article-title":"Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4)","volume":"114","author":"Bouhassira","year":"2005","journal-title":"PAIN\u00ae"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"395","DOI":"10.21037\/qims-21-126","article-title":"Assessment of peripheral neuropathy in type 2 diabetes by diffusion tensor imaging","volume":"12","author":"Wang","year":"2022","journal-title":"Quant. Imaging Med. Surg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"246","DOI":"10.15557\/JoU.2017.0036","article-title":"High resolution ultrasonography of the tibial nerve in diabetic peripheral neuropathy","volume":"17","author":"Singh","year":"2017","journal-title":"J. Ultrason."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1002\/ana.24524","article-title":"Magnetic resonance neurography detects diabetic neuropathy early and with Proximal Predominance","volume":"78","author":"Pham","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"113272","DOI":"10.1016\/j.expneurol.2020.113272","article-title":"Biology of the human blood-nerve barrier in health and disease","volume":"328","author":"Ubogu","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e00924","DOI":"10.1002\/brb3.924","article-title":"Fingolimod promotes blood\u2013nerve barrier properties in vitro","volume":"8","author":"Nishihara","year":"2018","journal-title":"Brain Behav."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.pain.2014.01.026","article-title":"Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief","volume":"155","author":"Lim","year":"2014","journal-title":"PAIN\u00ae"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s11064-011-0626-8","article-title":"Pericyte-derived Glial Cell Line-derived Neurotrophic Factor Increase the Expression of Claudin-5 in the Blood\u2013brain Barrier and the Blood-nerve Barrier","volume":"37","author":"Shimizu","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/s41593-020-0618-6","article-title":"Profiling peripheral nerve macrophages reveals two macrophage subsets with distinct localization, transcriptome and response to injury","volume":"23","author":"Ydens","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"113244","DOI":"10.1016\/j.expneurol.2020.113244","article-title":"Characteristics of the nerve barrier and the blood dorsal root ganglion barrier in health and disease","volume":"327","author":"Reinhold","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1210\/er.2003-0019","article-title":"Oxidative stress in the pathogenesis of diabetic neuropathy","volume":"25","author":"Vincent","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1196\/annals.1338.067","article-title":"Role of advanced glycation end products and their receptors in development of diabetic neuropathy","volume":"1043","author":"Wada","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1089\/ars.2021.0152","article-title":"Oxidative Stress and Mitochondrial Dysfunction Associated with Peripheral Neuropathy in Type 1 Diabetes","volume":"37","author":"Eftekharpour","year":"2022","journal-title":"Antioxid. Redox Signal"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbrc.2011.03.087","article-title":"Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: Old perspective with a new angle","volume":"408","author":"Negi","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1007\/s11033-025-11091-0","article-title":"Disruptions in nitric oxide homeostasis, lipid peroxidation-derived oxidative stress, and antioxidant defense mechanisms in spinal cord injury: Elucidating biomolecular correlates of disease severity","volume":"52","author":"Mursal","year":"2025","journal-title":"Mol. Biol. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/10623320490482619","article-title":"Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus","volume":"11","author":"Zou","year":"2004","journal-title":"Endothelium"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1111\/j.1476-5381.2008.00086.x","article-title":"Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction","volume":"156","author":"Szabo","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_65","first-page":"247861","article-title":"Peroxynitrite mediates diabetes-induced endothelial dysfunction: Possible role of Rho kinase activation","volume":"2010","author":"Tawfik","year":"2010","journal-title":"Exp. Diabetes Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1007\/s13167-010-0002-9","article-title":"Prediction of diabetic retinopathy: Role of oxidative stress and relevance of apoptotic biomarkers","volume":"1","author":"Smith","year":"2010","journal-title":"EPMA J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1007\/s11064-011-0695-8","article-title":"Protective effects of Salvianolic acid B on Schwann cells apoptosis induced by high glucose","volume":"37","author":"Sun","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.pharmthera.2015.11.003","article-title":"Nrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases","volume":"157","author":"Buendia","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"674987","DOI":"10.1155\/2014\/674987","article-title":"Neuroinflammation and oxidative stress in diabetic neuropathy: Futuristic strategies based on these targets","volume":"2014","author":"Sandireddy","year":"2014","journal-title":"Int. J. Endocrinol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"113222","DOI":"10.1016\/j.intimp.2024.113222","article-title":"GLP-1 analogue liraglutide attenuates CIH-induced cognitive deficits by inhibiting oxidative stress, neuroinflammation, and apoptosis via the Nrf2\/HO-1 and MAPK\/NF-\u03baB signaling pathways","volume":"142","author":"Lv","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.jep.2016.03.031","article-title":"Paeoniflorin protects Schwann cells against high glucose induced oxidative injury by activating Nrf2\/ARE pathway and inhibiting apoptosis","volume":"185","author":"Yang","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.2337\/diabetes.54.6.1615","article-title":"The pathobiology of diabetic complications: A unifying mechanism","volume":"54","author":"Brownlee","year":"2005","journal-title":"Diabetes"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/CIRCRESAHA.110.223545","article-title":"Oxidative stress and diabetic complications","volume":"107","author":"Giacco","year":"2010","journal-title":"Circ. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1161\/hc0702.104183","article-title":"Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: A mechanism for amplification of inflammatory responses","volume":"105","author":"Basta","year":"2002","journal-title":"Circulation"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1172\/JCI118175","article-title":"Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes","volume":"96","author":"Schmidt","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S1474-4422(12)70065-0","article-title":"Diabetic neuropathy: Clinical manifestations and current treatments","volume":"11","author":"Callaghan","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/s41598-020-79276-0","article-title":"A systematic review and meta-analysis of the serum lipid profile in prediction of diabetic neuropathy","volume":"11","author":"Cai","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1210\/endrev\/bnaa025","article-title":"Microvascular Dysfunction in Diabetes Mellitus and Cardiometabolic Disease","volume":"42","author":"Horton","year":"2021","journal-title":"Endocr. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"H852","DOI":"10.1152\/ajpheart.00015.2005","article-title":"Oxidized LDL induces mitochondrially associated reactive oxygen\/nitrogen species formation in endothelial cells","volume":"289","author":"Zmijewski","year":"2005","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Maiuolo, J., Gliozzi, M., Musolino, V., Carresi, C., Nucera, S., Macr\u00ec, R., Scicchitano, M., Bosco, F., Scarano, F., and Ruga, S. (2019). The Role of Endothelial Dysfunction in Peripheral Blood Nerve Barrier: Molecular Mechanisms and Pathophysiological Implications. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123022"},{"key":"ref_81","first-page":"371","article-title":"The Role of Inflammation in the Pathogenesis of Diabetic Peripheral Neuropathy: New Lessons from Experimental Studies and Clinical Implications","volume":"16","author":"Panou","year":"2025","journal-title":"Diabetes Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s00401-003-0704-3","article-title":"Enhanced expression of E-selectin on the vascular endothelium of peripheral nerve in critically ill patients with neuromuscular disorders","volume":"106","author":"Fenzi","year":"2003","journal-title":"Acta Neuropathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1007\/s001250050911","article-title":"The potential role of cell adhesion molecules in the pathogenesis of diabetic neuropathy","volume":"41","author":"Jude","year":"1998","journal-title":"Diabetologia"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Chong, Z.Z., and Souayah, N. (2025). Crumbling Pathogenesis and Biomarkers for Diabetic Peripheral Neuropathy. Biomedicines, 13.","DOI":"10.3390\/biomedicines13020413"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"14430","DOI":"10.1038\/s41598-024-65495-2","article-title":"Prevalence of peripheral neuropathy, amputation, and quality of life in patients with diabetes mellitus","volume":"14","author":"Perveen","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1097\/WCO.0000000000000723","article-title":"The challenges of diabetic polyneuropathy: A brief update","volume":"32","author":"Zochodne","year":"2019","journal-title":"Curr. Opin. Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S1359-6446(05)03637-8","article-title":"The role of neuroinflammation in neuropathic pain: Mechanisms and therapeutic targets","volume":"11","author":"Myers","year":"2006","journal-title":"Drug Discov. Today"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1186\/s12967-025-07075-0","article-title":"Macrophage polarization in diabetic vascular complications: Mechanistic insights and therapeutic targets","volume":"23","author":"Cao","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: Nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1186\/s12974-021-02365-y","article-title":"Tracking macrophages in diabetic neuropathy with two-color nanoemulsions for near-infrared fluorescent imaging and microscopy","volume":"18","author":"Nichols","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1042\/BST20140319","article-title":"The blood-brain barrier endothelium: A target for pro-inflammatory cytokines","volume":"43","author":"Rochfort","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.14336\/AD.2021.0126","article-title":"Role of Matrix Metalloproteinases in Myelin Abnormalities and Mechanical Allodynia in Rodents with Diabetic Neuropathy","volume":"12","author":"Deng","year":"2021","journal-title":"Aging Dis."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Nag, S. (2011). The Blood-Nerve Barrier: Structure and Functional Significance. The Blood-Brain and Other Neural Barriers: Reviews and Protocols, Humana Press.","DOI":"10.1007\/978-1-60761-938-3"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s00424-016-1920-8","article-title":"Barrier function in the peripheral and central nervous system-a review","volume":"469","author":"Reinhold","year":"2017","journal-title":"Pflug. Arch."},{"key":"ref_95","first-page":"e50062","article-title":"An in vivo assay to test blood vessel permeability","volume":"73","author":"Radu","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1136\/jnnp.35.2.156","article-title":"Permeability of blood nerve barriers in the diabetic rat","volume":"35","author":"Seneviratne","year":"1972","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/BF00690317","article-title":"FITC-Dextrans as tracers for macromolecular movements in the nervous system. A freeze-drying method for dextrans of various molecular sizes injected into normal animals","volume":"59","author":"Malmgren","year":"1983","journal-title":"Acta Neuropathol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5705","DOI":"10.1073\/pnas.91.12.5705","article-title":"Macromolecular permeability across the blood-nerve and blood-brain barriers","volume":"91","author":"Poduslo","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00441-023-03741-1","article-title":"The role of PLVAP in endothelial cells","volume":"392","author":"Denzer","year":"2023","journal-title":"Cell Tissue Res."},{"key":"ref_100","first-page":"2583","article-title":"Puerarin prevents high glucose-induced apoptosis of Schwann cells by inhibiting oxidative stress","volume":"7","author":"Wu","year":"2012","journal-title":"Neural Regen. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"316","DOI":"10.3803\/EnM.2017.32.3.316","article-title":"Effects of Incretin-Based Therapies on Diabetic Microvascular Complications","volume":"32","author":"Kang","year":"2017","journal-title":"Endocrinol. Metab."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Kawanami, D., Matoba, K., Sango, K., and Utsunomiya, K. (2016). Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17081223"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/jnc.14336","article-title":"Liraglutide ameliorated peripheral neuropathy in diabetic rats: Involvement of oxidative stress, inflammation and extracellular matrix remodeling","volume":"146","author":"Moustafa","year":"2018","journal-title":"J. Neurochem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.2337\/dc14-0865","article-title":"The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications","volume":"37","author":"Avogaro","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"200","DOI":"10.7555\/JBR.26.20110054","article-title":"Sitagliptin, sitagliptin and metformin, or sitagliptin and amitriptyline attenuate streptozotocin-nicotinamide induced diabetic neuropathy in rats","volume":"26","author":"Sharma","year":"2012","journal-title":"J. Biomed. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1111\/jnc.13439","article-title":"The dipeptidyl peptidase IV inhibitor vildagliptin suppresses development of neuropathy in diabetic rodents: Effects on peripheral sensory nerve function, structure and molecular changes","volume":"136","author":"Tsuboi","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Kuthati, Y., Rao, V.N., Huang, W.H., Busa, P., and Wong, C.S. (2023). Teneligliptin Co-Infusion Alleviates Morphine Tolerance by Inhibition of Spinal Microglial Cell Activation in Streptozotocin-Induced Diabetic Rats. Antioxidants, 12.","DOI":"10.3390\/antiox12071478"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.bbadis.2014.04.013","article-title":"Dipeptidyl peptidase-IV inhibition prevents blood-retinal barrier breakdown, inflammation and neuronal cell death in the retina of type 1 diabetic rats","volume":"1842","author":"Marques","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa2107519","article-title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","volume":"385","author":"Davies","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/s12933-022-01604-7","article-title":"Tirzepatide, a dual GIP\/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction","volume":"21","author":"Nauck","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"178345","DOI":"10.1016\/j.ejphar.2025.178345","article-title":"The role of GLP-1 receptor in pain disorders and its pharmacological properties","volume":"1008","author":"Jing","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Kuthati, Y., Davuluri, V.N.G., and Wong, C.S. (2025). Therapeutic Effects of GLP-1 Receptor Agonists and DPP-4 Inhibitors in Neuropathic Pain: Mechanisms and Clinical Implications. Biomolecules, 15.","DOI":"10.3390\/biom15050622"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Liu, C., Wu, T., and Ren, N. (2024). Glucagon-like peptide-1 receptor agonists for the management of diabetic peripheral neuropathy. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1268619"},{"key":"ref_114","first-page":"2977","article-title":"GLP-1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK\/NF-\u03baB signaling pathways in streptozotocin-induced diabetic rats","volume":"41","author":"Ma","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00125-023-06072-6","article-title":"Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy","volume":"67","author":"Dhanapalaratnam","year":"2024","journal-title":"Diabetologia"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1111\/j.1463-1326.2011.01431.x","article-title":"GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice","volume":"13","author":"Jolivalt","year":"2011","journal-title":"Diabetes Obes. Metab."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.2337\/db25-0158","article-title":"Incretin Receptors in the Peripheral Nervous System: Implications for Obesity Treatment and Peripheral Neuropathy","volume":"74","author":"Sparks","year":"2025","journal-title":"Diabetes"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1016\/j.clinph.2021.05.033","article-title":"Effect of exenatide on peripheral nerve excitability in type 2 diabetes","volume":"132","author":"Issar","year":"2021","journal-title":"Clin. Neurophysiol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1152\/jn.00228.2024","article-title":"Impact of glucagon-like peptide-1 receptor agonists on axonal function in diabetic peripheral neuropathy","volume":"133","author":"Dhanapalaratnam","year":"2025","journal-title":"J. Neurophysiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.jdiacomp.2015.07.013","article-title":"Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: Results from an 18-month proof-of-concept open-label randomized study","volume":"29","author":"Jaiswal","year":"2015","journal-title":"J. Diabetes Complicat."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"e16242","DOI":"10.1111\/jnc.16242","article-title":"Effect of the glucagon-like peptide-1 receptor agonists on diabetic peripheral neuropathy: A meta-analysis","volume":"169","author":"Fan","year":"2025","journal-title":"J. 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