{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:38:44Z","timestamp":1790642324451,"version":"4.1.0"},"reference-count":66,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Health and Welfare of Korea","award":["HI14C2284"],"award-info":[{"award-number":["HI14C2284"]}]},{"name":"the National Research Foundation of Korea supported by the Ministry of Science, ICT &amp; Future Planning","award":["NRF-2017R1C1B3002626"],"award-info":[{"award-number":["NRF-2017R1C1B3002626"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Methylglyoxal (MG) is a dicarbonyl compound, the level of which is increased in the blood of diabetes patients. MG is reported to be involved in the development of cerebrovascular complications in diabetes, but the exact mechanisms need to be elucidated. Here, we investigated the possible roles of oxidative stress and mitophagy in MG-induced functional damage in brain endothelial cells (ECs). Treatment of MG significantly altered metabolic stress as observed by the oxygen-consumption rate and barrier-integrity as found in impaired trans-endothelial electrical resistance in brain ECs. The accumulation of MG adducts and the disturbance of the glyoxalase system, which are major detoxification enzymes of MG, occurred concurrently. Reactive oxygen species (ROS)-triggered oxidative damage was observed with increased mitochondrial ROS production and the suppressed Akt\/hypoxia-inducible factor 1 alpha (HIF-1\u03b1) pathway. Along with the disturbance of mitochondrial bioenergetic function, parkin-1-mediated mitophagy was increased by MG. Treatment of N-acetyl cysteine significantly reversed mitochondrial damage and mitophagy. Notably, MG induced dysregulation of tight junction proteins including occludin, claudin-5, and zonula occluden-1 in brain ECs. Here, we propose that diabetic metabolite MG-associated oxidative stress may contribute to mitochondrial damage and autophagy in brain ECs, resulting in the dysregulation of tight junction proteins and the impairment of permeability.<\/jats:p>","DOI":"10.3390\/antiox9090820","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T08:40:26Z","timestamp":1599122426000},"page":"820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt\/HIF-1\u03b1 Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species"],"prefix":"10.3390","volume":"9","author":[{"given":"Donghyun","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyeong-A","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Hyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Hye","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0583-2116","authenticated-orcid":false,"given":"Ok-Nam","family":"Bae","sequence":"additional","affiliation":[{"name":"College of Pharmacy Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1161\/CIR.0000000000000034","article-title":"Type 1 diabetes mellitus and cardiovascular disease: A scientific statement from the American Heart Association and American Diabetes Association","volume":"130","author":"Fonseca","year":"2014","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1093\/cvr\/cvt013","article-title":"High glucose condition increases nadph oxidase activity in endothelial microparticles that promote vascular inflammation","volume":"98","author":"Jansen","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1248\/bpb.b14-00172","article-title":"High glucose condition induces autophagy in endothelial progenitor cells contributing to angiogenic impairment","volume":"37","author":"Kim","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Peng, C., Ma, J., Gao, X., Tian, P., Li, W., and Zhang, L. (2013). High glucose induced oxidative stress and apoptosis in cardiac microvascular endothelial cells are regulated by FoxO3a. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079739"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.clinbiochem.2010.11.004","article-title":"Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy","volume":"44","author":"Lu","year":"2011","journal-title":"Clin. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/0168-8227(89)90101-0","article-title":"The human red blood cell glyoxalase system in diabetes mellitus","volume":"7","author":"Thornalley","year":"1989","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1016\/j.clinbiochem.2007.07.016","article-title":"Proinflammatory and proapoptotic effects of methylglyoxal on neutrophils from patients with type 2 diabetes mellitus","volume":"40","author":"Wang","year":"2007","journal-title":"Clin. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1080\/15287394.2018.1440185","article-title":"Methylglyoxal induced advanced glycation end products (AGE)\/receptor for AGE (RAGE)-mediated angiogenic impairment in bone marrow-derived endothelial progenitor cells","volume":"81","author":"Kim","year":"2018","journal-title":"J. Toxicol. Environ. Health A"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Santini, S.J., Cordone, V., Mijit, M., Bignotti, V., Aimola, P., Dolo, V., Falone, S., and Amicarelli, F. (2019). SIRT1-Dependent Upregulation of Antiglycative Defense in HUVECs Is Essential for Resveratrol Protection against High Glucose Stress. Antioxidants, 8.","DOI":"10.3390\/antiox8090346"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.2337\/db15-0568","article-title":"Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy","volume":"65","author":"Vulesevic","year":"2016","journal-title":"Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.taap.2017.03.020","article-title":"The role of cPLA2 in Methylglyoxal-induced cell apoptosis of HUVECs","volume":"323","author":"Yuan","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1007\/s10495-014-0974-3","article-title":"LR-90 prevents methylglyoxal-induced oxidative stress and apoptosis in human endothelial cells","volume":"19","author":"Figarola","year":"2014","journal-title":"Apoptosis"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.neulet.2014.03.010","article-title":"Venlafaxine protects methylglyoxal-induced apoptosis in the cultured human brain microvascular endothelial cells","volume":"569","author":"Lv","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1111\/apha.12139","article-title":"Vaspin prevents methylglyoxal-induced apoptosis in human vascular endothelial cells by inhibiting reactive oxygen species generation","volume":"209","author":"Phalitakul","year":"2013","journal-title":"Acta Physiol. (Oxf.)"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1124\/pr.57.2.4","article-title":"The blood-brain barrier\/neurovascular unit in health and disease","volume":"57","author":"Hawkins","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/nm.3407","article-title":"Development, maintenance and disruption of the blood-brain barrier","volume":"19","author":"Obermeier","year":"2013","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.5487\/TR.2013.29.3.157","article-title":"Loss of Integrity: Impairment of the Blood-brain Barrier in Heavy Metal-associated Ischemic Stroke","volume":"29","author":"Kim","year":"2013","journal-title":"Toxicol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12987-020-00182-8","article-title":"Autophagy-mediated occludin degradation contributes to blood-brain barrier disruption during ischemia in bEnd.3 brain endothelial cells and rat ischemic stroke models","volume":"17","author":"Kim","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1161\/STROKEAHA.117.017287","article-title":"Role of Autophagy in Endothelial Damage and Blood-Brain Barrier Disruption in Ischemic Stroke","volume":"49","author":"Kim","year":"2018","journal-title":"Stroke"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.biopha.2018.09.058","article-title":"Molecular pathways associated with oxidative stress in diabetes mellitus","volume":"108","author":"Ighodaro","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.taap.2006.01.003","article-title":"Diabetes and mitochondrial function: Role of hyperglycemia and oxidative stress","volume":"212","author":"Rolo","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"297512","DOI":"10.1155\/2013\/297512","article-title":"Triggers and effectors of oxidative stress at blood-brain barrier level: Relevance for brain ageing and neurodegeneration","volume":"2013","author":"Enciu","year":"2013","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1161\/STROKEAHA.115.009099","article-title":"Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier","volume":"46","author":"Doll","year":"2015","journal-title":"Stroke"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"201","DOI":"10.5487\/TR.2019.35.2.201","article-title":"Comparative In Vitro Toxicity Study of Docetaxel and Nanoxel, a Docetaxel-Loaded Micellar Formulation Using Cultured and Blood Cells","volume":"35","author":"Do","year":"2019","journal-title":"Toxicol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Rellick, S.L., Hu, H., Simpkins, J.W., and Ren, X. (2016). Evaluation of Bioenergetic Function in Cerebral Vascular Endothelial Cells. J. Vis. Exp.","DOI":"10.3791\/54847-v"},{"key":"ref_27","first-page":"275","article-title":"Measurement of Mitochondrial Mass by Flow Cytometry during Oxidative Stress","volume":"4","author":"Doherty","year":"2017","journal-title":"React. Oxyg. Species (Apex)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1007\/s00726-010-0783-0","article-title":"Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome","volume":"42","author":"Rabbani","year":"2012","journal-title":"Amino Acids"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.gene.2015.08.009","article-title":"Pitfalls of the MTT assay: Direct and off-target effects of inhibitors can result in over\/underestimation of cell viability","volume":"574","author":"Stepanenko","year":"2015","journal-title":"Gene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.bbamcr.2010.08.006","article-title":"Hypoxia-inducible factor 1: Regulator of mitochondrial metabolism and mediator of ischemic preconditioning","volume":"1813","author":"Semenza","year":"2011","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3389\/fcell.2016.00011","article-title":"Hypoxia-Inducible Factors (HIFs) and Phosphorylation: Impact on Stability, Localization, and Transactivity","volume":"4","author":"Kietzmann","year":"2016","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1042\/BJ20110162","article-title":"Assessing mitochondrial dysfunction in cells","volume":"435","author":"Brand","year":"2011","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.freeradbiomed.2017.03.028","article-title":"Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells","volume":"108","author":"Dafre","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.3390\/nu5083311","article-title":"Dietary fructose feeding increases adipose methylglyoxal accumulation in rats in association with low expression and activity of glyoxalase-2","volume":"5","author":"Masterjohn","year":"2013","journal-title":"Nutrients"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1182\/blood-2011-10-387381","article-title":"HIF1alpha is required for survival maintenance of chronic myeloid leukemia stem cells","volume":"119","author":"Zhang","year":"2012","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1161\/STROKEAHA.114.005183","article-title":"Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage","volume":"45","author":"Baek","year":"2014","journal-title":"Stroke"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1038\/s41598-018-19930-w","article-title":"Mitochondrial biogenesis and metabolic hyperactivation limits the application of MTT assay in the estimation of radiation induced growth inhibition","volume":"8","author":"Rai","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Nigro, C., Leone, A., Raciti, G.A., Longo, M., Mirra, P., Formisano, P., Beguinot, F., and Miele, C. (2017). Methylglyoxal-Glyoxalase 1 Balance: The Root of Vascular Damage. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18010188"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1042\/CS20140683","article-title":"The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases","volume":"128","author":"Maessen","year":"2015","journal-title":"Clin. Sci. (Lond.)"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.semcdb.2011.02.015","article-title":"Glyoxalase in diabetes, obesity and related disorders","volume":"22","author":"Rabbani","year":"2011","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3109\/10715760903321788","article-title":"Methylglyoxal augments intracellular oxidative stress in human aortic endothelial cells","volume":"44","author":"Miyazawa","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.vph.2016.08.012","article-title":"Phosphocreatine protects endothelial cells from Methylglyoxal induced oxidative stress and apoptosis via the regulation of PI3K\/Akt\/eNOS and NF-kappaB pathway","volume":"91","author":"Chu","year":"2017","journal-title":"Vasc. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1039\/C4FO01110D","article-title":"Delta-Tocopherol prevents methylglyoxal-induced apoptosis by reducing ROS generation and inhibiting apoptotic signaling cascades in human umbilical vein endothelial cells","volume":"6","author":"Do","year":"2015","journal-title":"Food Funct."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7180943","DOI":"10.1155\/2017\/7180943","article-title":"Polydatin Prevents Methylglyoxal-Induced Apoptosis through Reducing Oxidative Stress and Improving Mitochondrial Function in Human Umbilical Vein Endothelial Cells","volume":"2017","author":"Pang","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s12020-020-02191-x","article-title":"Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells","volume":"68","author":"Liu","year":"2020","journal-title":"Endocrine"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1161\/CIRCRESAHA.117.311401","article-title":"Reactive Oxygen Species in Metabolic and Inflammatory Signaling","volume":"122","author":"Forrester","year":"2018","journal-title":"Circ. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1161\/CIRCRESAHA.111.300233","article-title":"Mitochondria and endothelial function","volume":"112","author":"Kluge","year":"2013","journal-title":"Circ. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"R170","DOI":"10.1016\/j.cub.2018.01.004","article-title":"Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance","volume":"28","author":"Pickles","year":"2018","journal-title":"Curr. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1007\/s00018-019-03039-y","article-title":"Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria","volume":"76","author":"Thomas","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Bento, C.F., Fernandes, R., Ramalho, J., Marques, C., Shang, F., Taylor, A., and Pereira, P. (2010). The chaperone-dependent ubiquitin ligase CHIP targets HIF-1alpha for degradation in the presence of methylglyoxal. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015062"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Costanzini, A., Sgarbi, G., Maresca, A., Del Dotto, V., Solaini, G., and Baracca, A. (2019). Mitochondrial Mass Assessment in a Selected Cell Line under Different Metabolic Conditions. Cells, 8.","DOI":"10.3390\/cells8111454"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s00125-018-4602-6","article-title":"Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes","volume":"61","author":"Monaco","year":"2018","journal-title":"Diabetologia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E268","DOI":"10.1152\/ajpendo.00314.2018","article-title":"Mitochondrial dysfunction in type 2 diabetes mellitus: An organ-based analysis","volume":"316","author":"Pinti","year":"2019","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1089\/ars.2010.3779","article-title":"The interplay between mitochondrial dynamics and mitophagy","volume":"14","author":"Twig","year":"2011","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"749","DOI":"10.4103\/1673-5374.249218","article-title":"Mitophagy links oxidative stress conditions and neurodegenerative diseases","volume":"14","author":"Shefa","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.molcel.2010.09.022","article-title":"Hypoxia-inducible factors and the response to hypoxic stress","volume":"40","author":"Majmundar","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"132","DOI":"10.3389\/fcell.2018.00132","article-title":"Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors","volume":"6","author":"Chen","year":"2018","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1021\/bi500046t","article-title":"The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs","volume":"53","author":"Xue","year":"2014","journal-title":"Biochemistry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s11010-007-9535-1","article-title":"Plasma methylglyoxal and glyoxal are elevated and related to early membrane alteration in young, complication-free patients with Type 1 diabetes","volume":"305","author":"Han","year":"2007","journal-title":"Mol. Cell. Biochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/nm.2750","article-title":"Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy","volume":"18","author":"Bierhaus","year":"2012","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1007\/s00125-012-2452-1","article-title":"Is diabetes an acquired disorder of reactive glucose metabolites and their intermediates?","volume":"55","author":"Fleming","year":"2012","journal-title":"Diabetologia"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1007\/s00125-010-1677-0","article-title":"Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress","volume":"53","author":"Brouwers","year":"2010","journal-title":"Diabetologia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"H1339","DOI":"10.1152\/ajpheart.01021.2013","article-title":"Effects of methylglyoxal on human cardiac fibroblast: Roles of transient receptor potential ankyrin 1 (TRPA1) channels","volume":"307","author":"Oguri","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1161\/CIRCRESAHA.116.303804","article-title":"Autophagy in vascular disease","volume":"116","author":"Grootaert","year":"2015","journal-title":"Circ. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/jnc.13277","article-title":"Autophagy protects human brain microvascular endothelial cells against methylglyoxal-induced injuries, reproducible in a cerebral ischemic model in diabetic rats","volume":"135","author":"Fang","year":"2015","journal-title":"J. Neurochem."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/9\/820\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:06:10Z","timestamp":1760177170000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/9\/820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,3]]},"references-count":66,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["antiox9090820"],"URL":"https:\/\/doi.org\/10.3390\/antiox9090820","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,3]]}}}