{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:14:13Z","timestamp":1786115653301,"version":"build-2736575974"},"reference-count":67,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T00:00:00Z","timestamp":1785628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Florida Legislative Grant","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Crohn\u2019s disease (CD) is a chronic inflammatory bowel disease with a rising incidence and prevalence worldwide. It is associated with Mycobacterium avium subspecies paratuberculosis (MAP). Current CD treatment strategies are based on anti-inflammatory therapies, including anti-TNF-\u03b1 drugs. These treatment options provide short-term benefits and are associated with numerous side effects in CD patients. Manuka honey is distinguished from other honey by its high content of methylglyoxal (MGO). MGO, a reactive metabolite, is also generated endogenously in macrophages during infection through glycolysis; however, the amount is insufficient to neutralize the ongoing infection and subsequent tissue damage. This study examined whether exogenous, low-dose MGO can modulate MAP-driven inflammatory and glycolysis- and lactate-associated markers in infected macrophages. THP-1 macrophages were infected with the CD-associated MAP strain and then treated with MGO doses at defined time intervals. We measured markers of M1-\/M2-like phenotype polarization, monocarboxylate transporters, lactate export, antioxidant responses, cytokines, and selected glycolysis- and lactate-associated markers at both the mRNA and protein levels. MGO reduced M1 signaling markers CXCL10 (p &lt; 0.05), TNF-\u03b1 (p &lt; 0.0001), IL-1\u03b2 (p &lt; 0.01), and IL-6 (p &lt; 0.0001). Simultaneously, MGO promoted M2 shift, elevating CD206 by 1.20-fold and IL-10 by 7-fold. Low-dose MGO administration was associated with increases in Nrf-2 (1.4-fold), HO-1 (1.4-fold), and IL-1Ra (1.5-fold), while the pro-inflammatory cytokines decreased. Metabolically, MGO downregulated MCT4 (p &lt; 0.01) and reduced lactate export by 30%. These changes were coupled with higher PHD2 (1.4-fold) and decreases in GLUT1 (0.9-fold), PKD1 (0.8-fold), and IL-1\u03b2, consistent with attenuated glycolysis- and lactate-associated inflammatory signaling. These results suggest that hormetic concentration of MGO mitigates MAP-induced inflammatory activation while altering glycolysis- and lactate-related signaling markers in infected macrophages. Most importantly, we unraveled the predicted molecular mechanism by which MGO suppresses inflammation and modulates oxidative damage.<\/jats:p>","DOI":"10.3390\/ijms27156940","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Methylglyoxal Attenuates Mycobacterium avium subspecies paratuberculosis (MAP)-Induced Pro-Inflammatory Macrophage Programming Associated with NRF-2 Antioxidant Responses and Reduced MCT4\/Lactate-Linked Inflammatory Markers"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-9340","authenticated-orcid":false,"given":"Heba R.","family":"Alrefaey","sequence":"first","affiliation":[{"name":"Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9222-4527","authenticated-orcid":false,"given":"Saleh A.","family":"Naser","sequence":"additional","affiliation":[{"name":"Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrd1986","article-title":"Evolving knowledge and therapy of inflammatory bowel disease","volume":"5","author":"Korzenik","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1128\/CMR.15.1.79-94.2002","article-title":"Clinical aspects and pathophysiology of inflammatory bowel disease","volume":"15","author":"Hendrickson","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3748\/wjg.v20.i1.91","article-title":"Inflammatory bowel disease: Pathogenesis","volume":"20","author":"Zhang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1053\/j.gastro.2023.07.003","article-title":"Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States","volume":"165","author":"Lewis","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.14309\/ajg.0000000000003465","article-title":"ACG clinical guideline: Management of Crohn\u2019s disease in adults","volume":"120","author":"Lichtenstein","year":"2025","journal-title":"Off. J. Am. Coll. Gastroenterol.|ACG"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/S0140-6736(04)17058-X","article-title":"Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn\u2019s disease","volume":"364","author":"Naser","year":"2004","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.3748\/wjg.v16.i36.4558","article-title":"High prevalence of viable Mycobacterium avium subspecies paratuberculosis in Crohn\u2019s disease","volume":"16","author":"Mendoza","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_8","first-page":"RA27","article-title":"Integrating theories of the etiology of Crohn\u2019s disease. On the etiology of Crohn\u2019s disease: Questioning the hypotheses","volume":"12","author":"Chamberlin","year":"2006","journal-title":"Med. Sci. Monit. Int. Med. J. Exp. Clin. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/S1473-3099(07)70211-6","article-title":"Mycobacterium avium subspecies paratuberculosis and Crohn\u2019s disease: A systematic review and meta-analysis","volume":"7","author":"Feller","year":"2007","journal-title":"Lancet Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/ibd.20276","article-title":"Detection of Mycobacterium avium subspecies paratuberculosis from patients with Crohn\u2019s disease using nucleic acid-based techniques: A systematic review and meta-analysis","volume":"14","author":"Abubakar","year":"2008","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Aitken, J.M., Aitken, J.E., and Agrawal, G. (2024). Mycobacterium avium ssp. paratuberculosis and Crohn\u2019s disease\u2014Diagnostic microbiological investigations can inform new therapeutic approaches. Antibiotics, 13.","DOI":"10.3390\/antibiotics13020158"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"28","DOI":"10.21037\/tgh-23-16","article-title":"Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn\u2019s disease: The debate continues","volume":"8","author":"Mintz","year":"2023","journal-title":"Transl. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e000216","DOI":"10.1136\/bmjgast-2018-000216","article-title":"TNF\u03b1 inhibitors exacerbate Mycobacterium paratuberculosis infection in tissue culture: A rationale for poor response of patients with Crohn\u2019s disease to current approved therapy","volume":"5","author":"Qasem","year":"2018","journal-title":"BMJ Open Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Alhendi, A., and Naser, S.A. (2024). In vitro neutralization of IL-6 receptor exacerbates damage to intestinal epithelial cells during Mycobacterium avium paratuberculosis infection. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1412800"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.gie.2007.02.060","article-title":"Postoperative endoscopic surveillance in Crohn\u2019s disease: Bottom up or top down?","volume":"66","author":"Katz","year":"2007","journal-title":"Gastrointest. Endosc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/ibd.20741","article-title":"Postoperative therapy for Crohn\u2019s disease","volume":"15","author":"Blum","year":"2009","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1016\/S0140-6736(14)61908-5","article-title":"Crohn\u2019s disease management after intestinal resection: A randomised trial","volume":"385","author":"Kamm","year":"2015","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Williams, N.C., and O\u2019Neill, L.A. (2018). A role for the Krebs cycle intermediate citrate in metabolic reprogramming in innate immunity and inflammation. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00141"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.4049\/jimmunol.1501612","article-title":"Cutting edge: Mycobacterium tuberculosis induces aerobic glycolysis in human alveolar macrophages that is required for control of intracellular bacillary replication","volume":"196","author":"Gleeson","year":"2016","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.chom.2017.07.020","article-title":"Legionella pneumophila modulates mitochondrial dynamics to trigger metabolic repurposing of infected macrophages","volume":"22","author":"Escoll","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.4049\/jimmunol.1600266","article-title":"HIF-1\u03b1 is an essential mediator of IFN-\u03b3\u2013dependent immunity to Mycobacterium tuberculosis","volume":"197","author":"Braverman","year":"2016","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.4049\/jimmunol.1701522","article-title":"Toll-like receptor 4\u2013induced glycolytic burst in human monocyte-derived dendritic cells results from p38-dependent stabilization of HIF-1\u03b1 and increased hexokinase II expression","volume":"201","author":"Diaz","year":"2018","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115986","DOI":"10.1016\/j.ejmech.2023.115986","article-title":"Research progress of hexokinase 2 in inflammatory-related diseases and its inhibitors","volume":"264","author":"Chen","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.redox.2017.04.018","article-title":"Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism","volume":"12","author":"Kalyanaraman","year":"2017","journal-title":"Redox Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11635","DOI":"10.1038\/ncomms11635","article-title":"HIF-1\u03b1-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity","volume":"7","author":"Semba","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.molmet.2019.07.006","article-title":"Monocarboxylate transporters in cancer","volume":"33","author":"Payen","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1074\/jbc.M114.603589","article-title":"The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages","volume":"290","author":"Tan","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5208","DOI":"10.1038\/s41467-022-32871-3","article-title":"Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2","volume":"13","author":"Feng","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhou, X., Zou, K., Chen, G., Huang, L., Yang, F., Pan, W., Xu, H., Xu, Z., and Chen, H. (2021). Monocarboxylate transporter 4 triggered cell pyroptosis to aggravate intestinal inflammation in inflammatory bowel disease. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.644862"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.diabres.2012.11.003","article-title":"Where does plasma methylglyoxal originate from?","volume":"99","author":"Kalapos","year":"2013","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tem.2019.10.003","article-title":"Methylglyoxal metabolism and aging-related disease: Moving from correlation toward causation","volume":"31","author":"Johannsen","year":"2020","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6366","DOI":"10.3390\/cimb46070380","article-title":"The Antioxidant Potential of Commercial Manuka Honey from New Zealand\u2014Biochemical and Cellular Studies","volume":"46","author":"Karwowski","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_34","first-page":"881","article-title":"Health benefits of manuka honey as an essential constituent for tissue regeneration","volume":"18","author":"Niaz","year":"2017","journal-title":"Curr. Drug Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/mnfr.200700282","article-title":"Identification and quantification of methylglyoxal as the dominant antibacterial constituent of Manuka (Leptospermum scoparium) honeys from New Zealand","volume":"52","author":"Mavric","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1002\/alr.20073","article-title":"Methylglyoxal: (active agent of manuka honey) in vitro activity against bacterial biofilms","volume":"1","author":"Kilty","year":"2011","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.chom.2025.05.026","article-title":"Methylglyoxal is an antibacterial effector produced by macrophages during infection","volume":"33","author":"Berry","year":"2025","journal-title":"Cell Host Microbe"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"111333","DOI":"10.1016\/j.fct.2020.111333","article-title":"Long-term intake of the reactive metabolite methylglyoxal is not toxic in mice","volume":"141","author":"Zunkel","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1080\/15384047.2016.1210736","article-title":"Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression","volume":"17","author":"He","year":"2016","journal-title":"Cancer Biol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Schmoch, T., Uhle, F., Siegler, B.H., Fleming, T., Morgenstern, J., Nawroth, P.P., Weigand, M.A., and Brenner, T. (2017). The glyoxalase system and methylglyoxal-derived carbonyl stress in sepsis: Glycotoxic aspects of sepsis pathophysiology. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030657"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.bbrc.2015.01.140","article-title":"Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease","volume":"458","author":"Rabbani","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Manfredelli, D., Torcoli, C., Pariano, M., Bellezza, G., Baroni, T., Talesa, V.N., Sidoni, A., and Antognelli, C. (2025). PTEN\/PKM2\/ER\u03b1-Driven Glyoxalase 1 Overexpression Sustains PC3 Prostate Cancer Cell Growth Through MG-H1\/RAGE Pathway Desensitization Leading to H2O2-Dependent KRIT1 Downregulation. Antioxidants, 14.","DOI":"10.3390\/antiox14091120"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.arr.2007.08.007","article-title":"Hormesis defined","volume":"7","author":"Mattson","year":"2008","journal-title":"Ageing Res. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"11624","DOI":"10.1038\/ncomms11624","article-title":"Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription","volume":"7","author":"Kobayashi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1093\/ibd\/izae092","article-title":"Overview to Challenges in IBD 2024\u20132029","volume":"30","author":"Heller","year":"2024","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Purnak, T., and Ertan, A. (2024). Optimal management of patients with moderate-to-severe inflammatory bowel disease. J. Clin. Med., 13.","DOI":"10.3390\/jcm13237026"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S2468-1253(24)00044-X","article-title":"Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn\u2019s disease: 3-year data from the prospective, multicentre PANTS cohort study","volume":"9","author":"Chanchlani","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"309","DOI":"10.5217\/ir.2024.00076","article-title":"Tuberculosis risk in patients with Crohn\u2019s disease on biologics: A retrospective analysis of the Japanese Medical Claims Database","volume":"23","author":"Fujimoto","year":"2025","journal-title":"Intest. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"qiaf037","DOI":"10.1093\/jleuko\/qiaf037","article-title":"Metabolic adaptations driving innate immune memory: Mechanisms and therapeutic implications","volume":"117","author":"Hao","year":"2025","journal-title":"J. Leukoc. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/s41586-018-0622-0","article-title":"A metabolite-derived protein modification integrates glycolysis with KEAP1\u2013NRF2 signalling","volume":"562","author":"Bollong","year":"2018","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"32","DOI":"10.21037\/atm-21-4958","article-title":"Genistein mitigates oxidative stress and inflammation by regulating Nrf2\/HO-1 and NF-\u03baB signaling pathways in hypoxic-ischemic brain damage in neonatal mice","volume":"10","author":"Li","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1042\/bj3290321","article-title":"Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past","volume":"329","author":"Price","year":"1998","journal-title":"Biochem. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1042\/bj3500219","article-title":"The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells","volume":"350","author":"Dimmer","year":"2000","journal-title":"Biochem. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"9030","DOI":"10.1074\/jbc.M511397200","article-title":"The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1\u03b1-dependent mechanism","volume":"281","author":"Ullah","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6655529","DOI":"10.1155\/2021\/6655529","article-title":"MCT4 promotes tumor malignancy in F98 glioma cells","volume":"2021","author":"Reuss","year":"2021","journal-title":"J. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1074\/jbc.RA119.011178","article-title":"Lactate production is a prioritized feature of adipocyte metabolism","volume":"295","author":"Krycer","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.cmet.2018.02.020","article-title":"The factor inhibiting HIF asparaginyl hydroxylase regulates oxidative metabolism and accelerates metabolic adaptation to hypoxia","volume":"27","author":"Sim","year":"2018","journal-title":"Cell Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41573-023-00848-6","article-title":"Targeting hypoxia-inducible factors: Therapeutic opportunities and challenges","volume":"23","author":"Yuan","year":"2024","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.cell.2011.03.054","article-title":"Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1","volume":"145","author":"Luo","year":"2011","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.1073\/pnas.082117899","article-title":"Structural basis for recruitment of CBP\/p300 by hypoxia-inducible factor-1\u03b1","volume":"99","author":"Freedman","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1101\/gad.924501","article-title":"FIH-1: A novel protein that interacts with HIF-1\u03b1 and VHL to mediate repression of HIF-1 transcriptional activity","volume":"15","author":"Mahon","year":"2001","journal-title":"Genes Dev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3109\/01913123.2016.1154914","article-title":"How methylglyoxal kills bacteria: An ultrastructural study","volume":"40","author":"Rabie","year":"2016","journal-title":"Ultrastruct. Pathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1080\/10715760500104025","article-title":"Review part of the series: From dietary antioxidants to regulators in cellular signalling and gene expression review: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C","volume":"39","author":"Duarte","year":"2005","journal-title":"Free Radic. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8958","DOI":"10.1021\/ja301994d","article-title":"Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones","volume":"134","author":"Wang","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Louis, T.J., Qasem, A., and Naser, S.A. (2022). Attenuation of Excess TNF-\u03b1 Release in Crohn\u2019s Disease by Silencing of iRHOMs 1\/2 and the Restoration of TGF-\u03b2 Mediated Immunosuppression Through Modulation of TACE Trafficking. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.887830"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1208\/s12248-020-00466-9","article-title":"In vitro and in vivo efficacy of AZD3965 and alpha-cyano-4-hydroxycinnamic acid in the murine 4T1 breast tumor model","volume":"22","author":"Guan","year":"2020","journal-title":"AAPS J."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Leone, A., Leone, A., Nigro, C., Nicol\u00f2, A., Prevenzano, I., Formisano, P., Beguinot, F., and Miele, C. (2021). The dual-role of methylglyoxal in tumor progression\u2013novel therapeutic approaches. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.645686"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6940\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T04:16:45Z","timestamp":1785989805000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6940"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,2]]},"references-count":67,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156940"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156940","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,2]]}}}