甲基乙二醛 (methylglyoxal, MGO)屬活性雙羰基化合物 (reactive dicarbonyl species, RCS)，為高度糖化終產物 (advanced glycation end products, AGEs)之前驅物，在體外可從日常飲食中獲得；在體內可經由糖解作用產生或透過視覺循環之副產物經代謝後生成。糖尿病患者長期處於高血糖狀態，其血液之MGO濃度顯著高於健康常人。已知MGO會促進AGEs生成，並活化AGE-RAGE signaling pathway，造成生物體氧化壓力與發炎反應，因此被認為可能是造成糖尿病視網膜病變的致病因子之一。據於此，本研究目的在於探討小鼠長期暴露於含MGO的飲食環境中，對於其視網膜是否會造成損傷效應。實驗選用七週齡C57BL/6雄性小鼠 (n = 24)，隨機分成健康控制組 (control group)、MGO組 (飲水中含1% MGO)，以及MGO + ALT-711組 (1 mg/kg body weight)，進行為期四十週的實驗。以hematoxylin and eosin (H&E) staining評估視網膜之組織病理變化；以免疫螢光染色 (immunofluorescence staining, IF)分析視網膜感光細胞、神經細胞活化、氧化壓力、發炎反應與AGE/RAGE等相關指標物的表現。結果顯示，長期給予MGO會降低小鼠視網膜組織外核層 (outer nuclear layer, ONL)、感光細胞內外段 (inner segment/outer segment, IS/OS)與內核層 (inner nuclear layer, INL)之厚度，並降低感光細胞之細胞核數，同時伴隨著視紫質 (rhodopsin)表現降低與膠質纖維酸性蛋白 (glial fibrillary acidic protein, GFAP)表現上升的現象。氧化壓力指標8-hydroxy-2-deoxyguanosine (8-OHdG)、促發炎細胞激素介白素1β (interleukin-1β, IL-1β )與腫瘤壞死因子 (tumor necrosis factor-α, TNF-α)於視網膜組織之表現，與控制組比較亦可見顯著上升的現象 (p < 0.05)；同時MGO主要代謝酵素乙二醛酶1 (glyoxalase-1, Glo-1)相較於控制組具有顯著降低的現象 (p < 0.05)。相反地，介入AGE抑制劑ALT-711後可減輕上述之負面效應。值得注意的是，MGO組之小鼠可見其視網膜組織有明顯Nδ -(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)累積與RAGE活化的現象。綜合上述， MGO可能經由促進AGEs生成與RAGE表現，造成視網膜組織之氧化壓力及發炎反應，進而導致感光細胞損傷與Müller神經細胞活化。本研究結果指出MGO對於視網膜健康之可能負面效應，並提出MGO在糖尿病視網膜病變過程中的可能損傷機制，建議日常膳食中應避免攝取含高MGO之食物。

Methylglyoxal (MGO) is a reactive dicarbonyl species (RCS) and a precursor of advanced glycation end products (AGEs). MGO can be formed from glycolysis or via the metabolism of visual cycle byproducts. Additionally, MGO can be obtained through the consumption of food. Patients with diabetes have chronic hyperglycemia, and their blood MGO levels are significantly higher than those of healthy individuals. It is well known that MGO can stimulate the production of AGEs and activate the AGE-RAGE signaling pathway, resulting in oxidative stress and inflammatory responses. MGO is therefore regarded as one of the pathogenic factors in diabetic retinopathy. This study aims to investigate whether long-term exposure to MGO causes retinal damage in mice. Twenty-four male C57BL/6 mice were randomly assigned into three groups: the control group (control), the MGO group (1% MGO in drinking water), and the MGO + ALT-711 group (1 mg/kg b.w.). Hematoxylin and eosin staining was used to analyze the histopathological changes of retinal tissue; immunofluorescence staining was used to analyze the expressions of relevant indicators such as photoreceptors, Müller cell activation, oxidative stress, inflammation, and AGEs accumulation. The results showed that administration of MGO for 40 weeks decreased the thickness of the outer nuclear layer (ONL), inner segment/outer segment (IS/OS), and inner nuclear layer (INL) of retinal tissue in mice, while reducing the number of photoreceptor cell nuclei and the expression levels of rhodopsin, and increasing the expression levels of glial fibrillary acidic protein (GFAP). The expressions of 8-hydroxy-2-deoxyguanosine (8-OHdG), IL-1β, and TNF-α increased significantly in the MGO group when compared to the control group (p < 0.05). On the contrary, the expression levels of glyoxalase-1 in the MGO group were significantly lower than in the control group (p < 0.05). The intervention of ALT-711, an AGE inhibitor, could alleviate these adverse effects. Notably, the mice in the MGO group showed accumulation of Nδ -(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1) and activation of receptor for advanced glycation end products (RAGE) in the retina. In conclusion, this study indicates that long-term administration of MGO causes retinal damage in mice, with the possible mechanism involving AGE/RAGE-induced oxidative stress and inflammation. Our study sheds lights on the potential impact of MGO on the progression of diabetic retinopathy and suggests avoiding foods high in MGO to preserve retinal health.

Al-Hawasi, A., & Lagali, N. (2022). Retinal ganglion cell layer thickness and volume measured by OCT changes with age, sex, and axial length in a healthy population. BMC ophthalmology, 22(1), 1-7.
Augustine, J., Troendle, E. P., Barabas, P., McAleese, C. A., Friedel, T., Stitt, A. W., & Curtis, T. M. (2021). The role of lipoxidation in the pathogenesis of diabetic retinopathy. Frontiers in endocrinology, 11, 621938.
B. Domènech, E., & Marfany, G. (2020). The relevance of oxidative stress in the pathogenesis and therapy of retinal dystrophies. Antioxidants, 9(4), 347.
Bautista-Pérez, R., Cano-Martínez, A., Gutiérrez-Velázquez, E., Martínez-Rosas, M., Pérez-Gutiérrez, R. M., Jiménez-Gómez, F., & Flores-Estrada, J. (2021). Spinach methanolic extract attenuates the retinal degeneration in diabetic rats. Antioxidants, 10(5), 717.
Bellier, J., Nokin, M. J., Lardé, E., Karoyan, P., Peulen, O., Castronovo, V., & Bellahcène, A. (2019). Methylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer. Diabetes Research and Clinical Practice, 148, 200-211.
Berner, A. K., Brouwers, O., Pringle, R., Klaassen, I., Colhoun, L., McVicar, C., ... & Stitt, A. W. (2012). Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology. Diabetologia, 55(3), 845-854.
Bhat, L. R., Vedantham, S., Krishnan, U. M., & Rayappan, J. B. B. (2019). Methylglyoxal–an emerging biomarker for diabetes mellitus diagnosis and its detection methods. Biosensors and bioelectronics, 133, 107-124.
Biosa, A., Outeiro, T. F., Bubacco, L., & Bisaglia, M. (2018). Diabetes mellitus as a risk factor for Parkinson’s disease: a molecular point of view. Molecular Neurobiology, 55(11), 8754-8763.
Boonpor, J., Petermann‐Rocha, F., Parra‐Soto, S., Pell, J. P., Gray, S. R., Celis‐Morales, C., & Ho, F. K. (2022). Types of diet, obesity, and incident type 2 diabetes: Findings from the UK Biobank prospective cohort study. Diabetes, Obesity and Metabolism, 24(7), 1351-1359.
Boote, C., Sigal, I. A., Grytz, R., Hua, Y., Nguyen, T. D., & Girard, M. J. (2020). Scleral structure and biomechanics. Progress in retinal and eye research, 74, 100773.
Brings, S., Fleming, T., Freichel, M., Muckenthaler, M. U., Herzig, S., & Nawroth, P. P. (2017). Dicarbonyls and advanced glycation end-products in the development of diabetic complications and targets for intervention. International journal of molecular sciences, 18(5), 984.
Brown, B. E., Nobecourt, E., Zeng, J., Jenkins, A. J., Rye, K. A., & Davies, M. J. (2013). Apolipoprotein AI glycation by glucose and reactive aldehydes alters phospholipid affinity but not cholesterol export from lipid-laden macrophages. PLoS One, 8(5), e65430.
Carter-Dawson, L., Zhang, Y., Harwerth, R. S., Rojas, R., Dash, P., Zhao, X. C., ... & Redell, J. B. (2010). Elevated albumin in retinas of monkeys with experimental glaucoma. Investigative Ophthalmology & Visual Science, 51(2), 952-959.
Chakraborty, S., Karmakar, K., & Chakravortty, D. (2014). Cells producing their own nemesis: understanding methylglyoxal metabolism. IUBMB life, 66(10), 667-678.
Chan, C. M., Huang, D. Y., Huang, Y. P., Hsu, S. H., Kang, L. Y., Shen, C. M., & Lin, W. W. (2016). Methylglyoxal induces cell death through endoplasmic reticulum stress‐associated ROS production and mitochondrial dysfunction. Journal of cellular and molecular medicine, 20(9), 1749-1760.
Chapot, C. A., Euler, T., & Schubert, T. (2017). How do horizontal cells ‘talk’to cone photoreceptors? Different levels of complexity at the cone–horizontal cell synapse. The Journal of physiology, 595(16), 5495-5506.
Chen, N. X., Srinivasan, S., O'Neill, K., Nickolas, T. L., Wallace, J. M., Allen, M. R., ... & Moe, S. M. (2020). Effect of advanced glycation end‐products (AGE) lowering drug ALT‐711 on biochemical, vascular, and bone parameters in a rat model of CKD‐MBD. Journal of Bone and Mineral Research, 35(3), 608-617.
Choi, Y. K. (2022). An Altered Neurovascular System in Aging-Related Eye Diseases. International Journal of Molecular Sciences, 23(22), 14104.
Coughlan, M. T., Forbes, J. M., & Cooper, M. E. (2007). Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Kidney international, 72, S54-S60.
Davis-Silberman, N., & Ashery-Padan, R. (2008). Iris development in vertebrates; genetic and molecular considerations. Brain Research, 1192, 17-28.
Degen, J., Hellwig, M., & Henle, T. (2012). 1, 2-Dicarbonyl compounds in commonly consumed foods. Journal of agricultural and food chemistry, 60(28), 7071-7079.
Degen, J., Vogel, M., Richter, D., Hellwig, M., & Henle, T. (2013). Metabolic transit of dietary methylglyoxal. Journal of agricultural and food chemistry, 61(43), 10253-10260.
Dhar, A., Desai, K. M., & Wu, L. (2010). Alagebrium attenuates acute methylglyoxal‐induced glucose intolerance in Sprague‐Dawley rats. British journal of pharmacology, 159(1), 166-175.
Dhar, A., Dhar, I., Bhat, A., & Desai, K. M. (2016). Alagebrium attenuates methylglyoxal induced oxidative stress and AGE formation in H9C2 cardiac myocytes. Life sciences, 146, 8-14.
Dietrich, N., Kolibabka, M., Busch, S., Bugert, P., Kaiser, U., Lin, J., et al. (2016). The DPP4 inhibitor linagliptin protects from experimental diabetic retinopathy. PloS one, 11(12), e0167853.
Ding, W. X., & Yin, X. M. (2012). Mitophagy: mechanisms, pathophysiological roles, and analysis. Biological chemistry, 393(7), 547-564.
Do, M. H., Hur, J., Choi, J., Kim, M., Kim, M. J., Kim, Y., & Ha, S. K. (2018). Eucommia ulmoides ameliorates glucotoxicity by suppressing advanced glycation end-products in diabetic mice kidney. Nutrients, 10(3), 265.
Dorenkamp, M., Müller, J. P., Shanmuganathan, K. S., Schulten, H., Müller, N., Löffler, I., et al. (2018). Hyperglycaemia-induced methylglyoxal accumulation potentiates VEGF resistance of diabetic monocytes through the aberrant activation of tyrosine phosphatase SHP-2/SRC kinase signalling axis. Scientific reports, 8(1), 1-13.
Dorgaleleh, S., Naghipoor, K., Barahouie, A., Dastaviz, F., & Oladnabi, M. (2020). Molecular and biochemical mechanisms of human iris color: a comprehensive review. Journal of Cellular Physiology, 235(12), 8972-8982.
Dube, G., Tiamiou, A., Bizet, M., Boumahd, Y., Gasmi, I., Crake, R., et al. (2023). Methylglyoxal: a novel upstream regulator of DNA methylation. Journal of Experimental & Clinical Cancer Research, 42(1), 78.
El-Hakeem, A. G., Kotb, H. G., Ahmed, A. M., & Youness, E. R. (2021). Study of plasma methylglyoxal level in patients with type II diabetes mellitus. The Scientific Journal of Al-Azhar Medical Faculty, Girls, 5(2), 257-264.
ElSayed, N. A., Aleppo, G., Aroda, V. R., Bannuru, R. R., Brown, F. M., Bruemmer, D., et al. (2023). 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes—2023. Diabetes Care, 46(Supplement_1), S19-S40.
Eshaq, R. S., Wright, W. S., & Harris, N. R. (2014). Oxygen delivery, consumption, and conversion to reactive oxygen species in experimental models of diabetic retinopathy. Redox biology, 2, 661-666.
Espana, E. M., & Birk, D. E. (2020). Composition, structure and function of the corneal stroma. Experimental eye research, 198, 108137.
Euler, T., Haverkamp, S., Schubert, T., & Baden, T. (2014). Retinal bipolar cells: elementary building blocks of vision. Nature Reviews Neuroscience, 15(8), 507-519.
Fallah, F., Alijanpour, M., Khafri, S., Pournasrollah, M., & Talebi, G. A. (2022). The effect of neuromuscular electrical stimulation on serum glucose levels in children and adolescents with type-1 diabetes mellitus: a single group clinical trial. BMC Endocrine Disorders, 22(1), 1-9.
Fernández-Sánchez, L., Lax, P., Campello, L., Pinilla, I., & Cuenca, N. (2015). Astrocytes and Müller cell alterations during retinal degeneration in a transgenic rat model of retinitis pigmentosa. Frontiers in cellular neuroscience, 9, 484.
Fosmark, D. S., Berg, J. P., Jensen, A. B., Sandvik, L., Agardh, E., Agardh, C. D., & Hanssen, K. F. (2009). Increased retinopathy occurrence in type 1 diabetes patients with increased serum levels of the advanced glycation endproduct hydroimidazolone. Acta ophthalmologica, 87(5), 498-500.
Frandsen, J. R., & Narayanasamy, P. (2018). Neuroprotection through flavonoid: Enhancement of the glyoxalase pathway. Redox biology, 14, 465-473.
Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., ... & Martín, C. (2020). Pathophysiology of type 2 diabetes mellitus. International journal of molecular sciences, 21(17), 6275.
Gomułka, K., & Ruta, M. (2023). The Role of Inflammation and Therapeutic Concepts in Diabetic Retinopathy—A Short Review. International Journal of Molecular Sciences, 24(2), 1024.
Hellwig, M., Gensberger-Reigl, S., Henle, T., & Pischetsrieder, M. (2018). Food-derived 1, 2-dicarbonyl compounds and their role in diseases. Seminars in Cancer Biology, 49, 1-8.
Hsu, W. H., Lee, B. H., Chang, Y. Y., Hsu, Y. W., & Pan, T. M. (2013). A novel natural Nrf2 activator with PPARγ-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia. Toxicology and applied pharmacology, 272(3), 842-851.
Jadeja, R. N., & Martin, P. M. (2021). Oxidative stress and inflammation in retinal degeneration. Antioxidants, 10(5), 790.
Jenkins, A. J., Joglekar, M. V., Hardikar, A. A., Keech, A. C., O'Neal, D. N., & Januszewski, A. S. (2015). Biomarkers in diabetic retinopathy. The review of diabetic studies: RDS, 12(1-2), 159.
Jia, X., Zhong, Z., Bao, T., Wang, S., Jiang, T., Zhang, Y., et al. (2020). Evaluation of early retinal nerve injury in type 2 diabetes patients without diabetic retinopathy. Frontiers in Endocrinology, 11, 475672.
Jung, E., Park, S. B., Jung, W. K., Kim, H. R., & Kim, J. (2019). Antiglycation activity of aucubin in vitro and in exogenous methylglyoxal injected rats. Molecules, 24(20), 3653.
Kaludercic, N., & Di Lisa, F. (2020). Mitochondrial ROS formation in the pathogenesis of diabetic cardiomyopathy. Frontiers in Cardiovascular Medicine, 7, 12.
Kamiya, E., Morita, A., Mori, A., Sakamoto, K., & Nakahara, T. (2023). The process of methylglyoxal-induced retinal capillary endothelial cell degeneration in rats. Microvascular Research, 146, 104455.
Kang, Q., Dai, H., Jiang, S., & Yu, L. (2022). Advanced glycation end products in diabetic retinopathy and phytochemical therapy. Frontiers in Nutrition, 9.
Kels, B. D., Grzybowski, A., & Grant-Kels, J. M. (2015). Human ocular anatomy. Clinics in dermatology, 33(2), 140-146.
Kern, T. S., & Engerman, R. L. (1995). Vascular lesions in diabetes are distributed non-uniformly within the retina. Experimental eye research, 60(5), 545-549.
Kim, J., Son, J. W., Lee, J. A., Oh, Y. S., & Shinn, S. H. (2004). Methylglyoxal induces apoptosis mediated by reactive oxygen species in bovine retinal pericytes. Journal of Korean medical science, 19(1), 95-100.
Kowluru, R. A., & Chan, P. S. (2007). Oxidative stress and diabetic retinopathy. Experimental diabetes research, 2007.
Kowluru, R. A., Atasi, L., & Ho, Y. S. (2006). Role of mitochondrial superoxide dismutase in the development of diabetic retinopathy. Investigative ophthalmology & visual science, 47(4), 1594-1599.
Kuzan, A. (2021). Toxicity of advanced glycation end products. Biomedical Reports, 14(5), 1-8.
Lai, S. W. T., Lopez Gonzalez, E. D. J., Zoukari, T., Ki, P., & Shuck, S. C. (2022). Methylglyoxal and its adducts: Induction, repair, and association with disease. Chemical Research in Toxicology, 35(10), 1720-1746.
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020). The cell biology of the retinal pigment epithelium. Progress in retinal and eye research, 78, 100846.
Lamb, T. D. (2022). Photoreceptor physiology and evolution: cellular and molecular basis of rod and cone phototransduction. The Journal of Physiology, 600(21), 4585-4601.
Lecleire-Collet, A., Tessier, L. H., Massin, P., Forster, V., Brasseur, G., Sahel, J. A., & Picaud, S. (2005). Advanced glycation end products can induce glial reaction and neuronal degeneration in retinal explants. British Journal of Ophthalmology, 89(12), 1631-1633.
Lenahan, C., Sanghavi, R., Huang, L., & Zhang, J. H. (2020). Rhodopsin: a potential biomarker for neurodegenerative diseases. Frontiers in Neuroscience, 14, 326.
Leone, A., Nigro, C., Nicolò, A., Prevenzano, I., Formisano, P., Beguinot, F., & Miele, C. (2021). The dual-role of methylglyoxal in tumor progression–novel therapeutic approaches. Frontiers in Oncology, 11, 645686.
Lin, K. Y., Hsih, W. H., Lin, Y. B., Wen, C. Y., & Chang, T. J. (2021). Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy. Journal of Diabetes Investigation, 12(8), 1322-1325.
Lin, N. H., Yang, A. W., Chang, C. H., & Perng, M. D. (2021). Elevated GFAP isoform expression promotes protein aggregation and compromises astrocyte function. The FASEB Journal, 35(5), e21614.
Liu, Y., Zeng, S., Ji, W., Yao, H., Lin, L., Cui, H., et al. (2022). Emerging theranostic nanomaterials in diabetes and its complications. Advanced Science, 9(3), 2102466.
Lo, T. W., Selwood, T., & Thornalley, P. J. (1994). The reaction of methylglyoxal with aminoguanidine under physiological conditions and prevention of methylglyoxal binding to plasma proteins. Biochemical pharmacology, 48(10), 1865-1870.
Lujan, B. J., Roorda, A., Croskrey, J. A., Dubis, A. M., Cooper, R. F., Bayabo, J. K., ... & Carroll, J. (2015). Directional optical coherence tomography provides accurate outer nuclear layer and Henle fiber layer measurements. Retina (Philadelphia, Pa.), 35(8), 1511.
M Santos, J., Mohammad, G., Zhong, Q., & A Kowluru, R. (2011). Diabetic retinopathy, superoxide damage and antioxidants. Current pharmaceutical biotechnology, 12(3), 352-361.
Ma, Y., Liu, F., & Xu, Y. (2019). Protective effect of β-glucogallin on damaged cataract against methylglyoxal induced oxidative stress in cultured lens epithelial cells. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 25, 9310.
Maasen, K., Eussen, S. J., Dagnelie, P. C., Houben, A. J., Webers, C. A., Schram, M. T., et al. (2022). Habitual intake of dietary methylglyoxal is associated with less low-grade inflammation: the Maastricht Study. The American Journal of Clinical Nutrition.
Maasen, K., Eussen, S. J., Scheijen, J. L., van der Kallen, C. J., Dagnelie, P. C., Opperhuizen, A., et al. (2022). Higher habitual intake of dietary dicarbonyls is associated with higher corresponding plasma dicarbonyl concentrations and skin autofluorescence: the Maastricht Study. The American journal of clinical nutrition, 115(1), 34-44.
Macchi, B., Di Paola, R., Marino-Merlo, F., Rosa Felice, M., Cuzzocrea, S., & Mastino, A. (2015). Inflammatory and cell death pathways in brain and peripheral blood in Parkinson’s disease. CNS & neurological disorders-drug targets (formerly Current drug targets-CNS & neurological disorders), 14(3), 313-324.
Mannu, G. S. (2014). Retinal phototransduction. Neurosciences Journal, 19(4), 275-280.
Masri, R. A., Weltzien, F., Purushothuman, S., Lee, S. C., Martin, P. R., & Grünert, U. (2021). Composition of the inner nuclear layer in human retina. Investigative Ophthalmology & Visual Science, 62(9), 22-22.
Medeiros, M. L., de Oliveira, M. G., Tavares, E. G., Mello, G. C., Anhe, G. F., Monica, F. Z., & Antunes, E. (2020). Long-term methylglyoxal intake aggravates murine Th2-mediated airway eosinophil infiltration. International immunopharmacology, 81, 106254.
Meek, K. M., & Boote, C. (2004). The organization of collagen in the corneal stroma. Experimental eye research, 78(3), 503-512.
Michel, M., Hess, C., Kaps, L., Kremer, W., Hilscher, M., Galle, P., et al. (2022). Elevated serum levels of methylglyoxal are associated with impaired liver function in patients with liver cirrhosis. Zeitschrift für Gastroenterologie, 60(01), P-2.
Mojadami, S., Ahangarpour, A., Mard, S. A., & Khorsandi, L. (2023). Diabetic nephropathy induced by methylglyoxal: gallic acid regulates kidney microRNAs and glyoxalase1–Nrf2 in male mice. Archives of Physiology and Biochemistry, 129(3), 655-662.
Muthyalaiah, Y. S., Jonnalagadda, B., John, C. M., & Arockiasamy, S. (2022). Impact of Advanced Glycation End products (AGEs) and its receptor (RAGE) on cancer metabolic signaling pathways and its progression. Glycoconjugate Journal, 1-18.
Nickla, D. L., & Wallman, J. (2010). The multifunctional choroid. Progress in retinal and eye research, 29(2), 144-168.
Nigro, C., Leone, A., Raciti, G. A., Longo, M., Mirra, P., Formisano, P., et al. (2017). Methylglyoxal-glyoxalase 1 balance: The root of vascular damage. International journal of molecular sciences, 18(1), 188.
Nowak, J. Z. (2013). Oxidative stress, polyunsaturated fatty acids-derived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration. Pharmacological reports, 65(2), 288-304.
Oliveira, A. L., de Oliveira, M. G., Medeiros, M. L., Mónica, F. Z., & Antunes, E. (2021). Metformin abrogates the voiding dysfunction induced by prolonged methylglyoxal intake. European Journal of Pharmacology, 910, 174502.
Oshitari, T. (2022). Diabetic retinopathy: Neurovascular disease requiring neuroprotective and regenerative therapies. Neural Regeneration Research, 17(4), 795.
Otamas, A., Grant, P. J., & Ajjan, R. A. (2020). Diabetes and atherothrombosis: The circadian rhythm and role of melatonin in vascular protection. Diabetes and Vascular Disease Research, 17(3), 1479164120920582.
Peppa, M., Brem, H., Cai, W., Zhang, J. G., Basgen, J., Li, Z., et al. (2006). Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711). American journal of nephrology, 26(5), 430-436.
Perween, S., Abidi, M., & Faizy, A. F. (2022). Biophysical changes in methylglyoxal modified fibrinogen and its role in the immunopathology of type 2 diabetes mellitus. International Journal of Biological Macromolecules, 202, 199-214.
Picconi, F., Parravano, M., Sciarretta, F., Fulci, C., Nali, M., Frontoni, S., et al. (2019). Activation of retinal Müller cells in response to glucose variability. Endocrine, 65, 542-549.
Piuri, G., Basello, K., Rossi, G., Soldavini, C. M., Duiella, S., Privitera, G., et al. (2020). Methylglyoxal, glycated albumin, PAF, and TNF-α: possible inflammatory and metabolic biomarkers for management of gestational diabetes. Nutrients, 12(2), 479.
Plows, J. F., Stanley, J. L., Baker, P. N., Reynolds, C. M., & Vickers, M. H. (2018). The pathophysiology of gestational diabetes mellitus. International journal of molecular sciences, 19(11), 3342.
Ptito, M., Bleau, M., & Bouskila, J. (2021). The retina: A window into the brain. Cells, 10(12), 3269.
Rabbani, N., & Thornalley, P. J. (2015). Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease. Biochemical and biophysical research communications, 458(2), 221-226.
Rabbani, N., & Thornalley, P. J. (2022). Emerging Glycation-Based Therapeutics—Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors. International Journal of Molecular Sciences, 23(5), 2453.
Rabbani, N., Xue, M., & Thornalley, P. J. (2014). Activity, regulation, copy number and function in the glyoxalase system. Biochemical Society transactions, 42(2), 419-424.
Rabbani, N., Xue, M., & Thornalley, P. J. (2021). Dicarbonyl stress, protein glycation and the unfolded protein response. Glycoconjugate Journal, 38(3), 331-340.
Ren, J., Zhang, S., Pan, Y., Jin, M., Li, J., Luo, Y., et al. (2022). Diabetic retinopathy: Involved cells, biomarkers, and treatments. Frontiers in Pharmacology, 13.
Rodrigues, T., Matafome, P., Sereno, J., Almeida, J., Castelhano, J., Gamas, L., et al. (2017). Methylglyoxal-induced glycation changes adipose tissue vascular architecture, flow and expansion, leading to insulin resistance. Scientific reports, 7(1), 1698.
Rojas, A., González, I., Morales, E., Pérez-Castro, R., Romero, J., & Figueroa, H. (2011). Diabetes and cancer: looking at the multiligand/RAGE axis. World journal of diabetes, 2(7), 108.
Rossino, M. G., Dal Monte, M., & Casini, G. (2019). Relationships between neurodegeneration and vascular damage in diabetic retinopathy. Frontiers in Neuroscience, 13, 1172.
Ryan, A. K., Rich, W., & Reilly, M. A. (2023). Oxidative stress in the brain and retina after traumatic injury. Frontiers in Neuroscience, 17, 1021152.
S Stem, M., & W Gardner, T. (2013). Neurodegeneration in the pathogenesis of diabetic retinopathy: molecular mechanisms and therapeutic implications. Current medicinal chemistry, 20(26), 3241-3250.
Sachdeva, M. M. (2021). Retinal neurodegeneration in diabetes: an emerging concept in diabetic retinopathy. Current diabetes reports, 21(12), 65.
Sachdeva, R., Schlotterer, A., Schumacher, D., Matka, C., Mathar, I., Dietrich, N., et al. (2018). TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation. Molecular metabolism, 9, 156-167.
Sajovic, J., Meglič, A., Glavač, D., Markelj, Š., Hawlina, M., & Fakin, A. (2022). The role of vitamin A in retinal diseases. International journal of molecular sciences, 23(3), 1014.
Sarthy, P. V., Fu, M., & Huang, J. (1991). Developmental expression of the glial fibrillary acidic protein (GFAP) gene in the mouse retina. Cellular and molecular neurobiology, 11, 623-637.
Schalkwijk, C. G., & Stehouwer, C. D. A. (2020). Methylglyoxal, a highly reactive dicarbonyl compound, in diabetes, its vascular complications, and other age-related diseases. Physiological reviews, 100(1), 407-461.
Schlotterer, A., Kolibabka, M., Lin, J., Acunman, K., Dietrichá, N., Sticht, C., et al. (2019). Methylglyoxal induces retinopathy‐type lesions in the absence of hyperglycemia: studies in a rat model. The FASEB Journal, 33(3), 4141-4153.
Sekar, P., Hsiao, G., Hsu, S. H., Huang, D. Y., Lin, W. W., & Chan, C. M. (2023). Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1. Redox Biology, 102786.
Sena, C. M., Matafome, P., Crisóstomo, J., Rodrigues, L., Fernandes, R., Pereira, P., & Seica, R. M. (2012). Methylglyoxal promotes oxidative stress and endothelial dysfunction. Pharmacological Research, 65(5), 497-506.
Shangari, N., Depeint, F., Furrer, R., Bruce, W. R., & O’Brien, P. J. (2005). The effects of partial thiamin deficiency and oxidative stress (ie, glyoxal and methylglyoxal) on the levels of α-oxoaldehyde plasma protein adducts in Fischer 344 rats. FEBS letters, 579(25), 5596-5602.
Sruthi, C. R., & Raghu, K. G. (2022). Methylglyoxal induces ambience for cancer promotion in HepG2 cells via Warburg effect and promotes glycation. Journal of Cellular Biochemistry.
Strauss, O. (2005). The retinal pigment epithelium in visual function. Physiological reviews, 85(3), 845-881.
Sveen, K. A., Bech Holte, K., Svanteson, M., Hanssen, K. F., Nilsson, J., Bengtsson, E., & Julsrud Berg, T. (2021). Autoantibodies against methylglyoxal-modified apolipoprotein B100 and apob100 peptide are associated with less coronary artery atherosclerosis and retinopathy in long-term type 1 diabetes. Diabetes Care, 44(6), 1402-1409.
Taguchi, K., & Fukami, K. (2023). RAGE signaling regulates the progression of diabetic complications. Frontiers in Pharmacology, 14, 1128872.
Tang, L., Xu, G. T., & Zhang, J. F. (2023). Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy. Neural Regeneration Research, 18(5), 976-982.
Thallas-Bonke, V., Lindschau, C., Rizkalla, B., Bach, L. A., Boner, G., Meier, M., et al. (2004). Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-α− dependent pathway. Diabetes, 53(11), 2921-2930.
Thompson, K., Chen, J., Luo, Q., Xiao, Y., Cummins, T. R., & Bhatwadekar, A. D. (2018). Advanced glycation end (AGE) product modification of laminin downregulates Kir4. 1 in retinal Müller cells. PLoS One, 13(2), e0193280.
Todoriki, S., Hosoda, Y., Yamamoto, T., Watanabe, M., Sekimoto, A., Sato, H., ... & Sato, E. (2022). Methylglyoxal induces inflammation, metabolic modulation and oxidative stress in myoblast cells. Toxins, 14(4), 263.
Toprak, C., & Yigitaslan, S. (2019). Alagebrium and complications of diabetes mellitus. The Eurasian Journal of Medicine, 51(3), 285.
Toriumi, K., Miyashita, M., Suzuki, K., Tabata, K., Horiuchi, Y., Ishida, H., et al. (2021). Role of glyoxalase 1 in methylglyoxal detoxification–the broad player of psychiatric disorders. Redox biology, 102222.
Trachsel-Moncho, L., Benlloch-Navarro, S., Fernández-Carbonell, Á., Ramírez-Lamelas, D. T., Olivar, T., Silvestre, D., ... & Miranda, M. (2018). Oxidative stress and autophagy-related changes during retinal degeneration and development. Cell death & disease, 9(8), 812.
Tsin, A., Betts-Obregon, B., & Grigsby, J. (2018). Visual cycle proteins: structure, function, and roles in human retinal disease. Journal of Biological Chemistry, 293(34), 13016-13021.
Upadhyay, M., Milliner, C., Bell, B. A., & Bonilha, V. L. (2020). Oxidative stress in the retina and retinal pigment epithelium (RPE): Role of aging, and DJ-1. Redox Biology, 37, 101623.
Uribarri, J., Woodruff, S., Goodman, S., Cai, W., Chen, X. U. E., Pyzik, R., et al. (2010). Advanced glycation end products in foods and a practical guide to their reduction in the diet. Journal of the American Dietetic Association, 110(6), 911-916.
Wang, G., Wang, Y., Yang, Q., Xu, C., Zheng, Y., Wang, L., ... & Luo, M. (2022). Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Cell Death & Disease, 13(1), 29.
Wang, J., Lin, J., Schlotterer, A., Wu, L., Fleming, T., Busch, S., ... & Hammes, H. P. (2014). CD74 indicates microglial activation in experimental diabetic retinopathy and exogenous methylglyoxal mimics the response in normoglycemic retina. Acta diabetologica, 51, 813-821.
Wang, K., & Pierscionek, B. K. (2019). Biomechanics of the human lens and accommodative system: Functional relevance to physiological states. Progress in retinal and eye research, 71, 114-131.
Watanabe, K., Okada, K., Fukabori, R., Hayashi, Y., Asahi, K., Terawaki, H., et al. (2014). Methylglyoxal (MG) and cerebro-renal interaction: does long-term orally administered MG cause cognitive impairment in normal Sprague-Dawley rats?. Toxins, 6(1), 254-269.
Wei, L., Mo, W., Lan, S., Yang, H., Huang, Z., Liang, X., ... & Luo, Z. (2022). GLP-1 RA Improves Diabetic Retinopathy by Protecting the Blood-Retinal Barrier through GLP-1R-ROCK-p-MLC Signaling Pathway. Journal of Diabetes Research, 2022.
Wilding, C., Bell, K., Funke, S., Beck, S., Pfeiffer, N., & Grus, F. H. (2015). GFAP antibodies show protective effect on oxidatively stressed neuroretinal cells via interaction with ERP57. Journal of pharmacological sciences, 127(3), 298-304.
Wolffenbuttel, B. H., Boulanger, C. M., Crijns, F. R., Huijberts, M. S., Poitevin, P., Swennen, G. N., ... & Lévy, B. I. (1998). Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proceedings of the National Academy of Sciences, 95(8), 4630-4634.
Wu, K. H. C., Madigan, M. C., Billson, F. A., & Penfold, P. L. (2003). Differential expression of GFAP in early v late AMD: a quantitative analysis. British journal of ophthalmology, 87(9), 1159-1166.
Wu, Y., Dong, L., Wu, Y., Wu, D., Zhang, Y., & Wang, S. (2021). Effect of methylglyoxal on the alteration in structure and digestibility of α‐lactalbumin, and the formation of advanced glycation end products under simulated thermal processing. Food Science & Nutrition, 9(4), 2299-2307.
Xiao, J., Adil, M. Y., Chang, K., Yu, Z., Yang, L., Utheim, T. P., ... & Cho, K. S. (2019). Visual contrast sensitivity correlates to the retinal degeneration in rhodopsin knockout mice. Investigative Ophthalmology & Visual Science, 60(13), 4196-4204.
Xue, J., Ray, R., Singer, D., Böhme, D., Burz, D. S., Rai, V., et al. (2014). The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs. Biochemistry, 53(20), 3327-3335.
Yang, A. Y., Chow, J., & Liu, J. (2018). Focus: sensory biology and pain: corneal innervation and sensation: the eye and beyond. The Yale journal of biology and medicine, 91(1), 13.
Yang, S., Zhou, J., & Li, D. (2021). Functions and diseases of the retinal pigment epithelium. Frontiers in pharmacology, 12, 727870.
Yue, Q., Song, Y., Liu, Z., Zhang, L., Yang, L., & Li, J. (2022). Receptor for advanced glycation end products (RAGE): A pivotal hub in immune diseases. Molecules, 27(15), 4922.
Yun, J. H. (2021). Interleukin-1β induces pericyte apoptosis via the NF-κB pathway in diabetic retinopathy. Biochemical and Biophysical Research Communications, 546, 46-53.
Zhang, B., He, K., Chen, W., Cheng, X., Cui, H., Zhong, W., ... & Wang, L. (2014). Alagebrium (ALT-711) improves the anti-hypertensive efficacy of nifedipine in diabetic-hypertensive rats. Hypertension Research, 37(10), 901-907.
Zhang, X., Scheijen, J. L., Stehouwer, C. D., Wouters, K., & Schalkwijk, C. G. (2023). Increased methylglyoxal formation in plasma and tissues during a glucose tolerance test is derived from exogenous glucose. Clinical Science, 137(8), 697-706.
Zhang, Y., Zhan, L., Wen, Q., Feng, Y., Luo, Y., & Tan, T. (2022). Trapping Methylglyoxal by Taxifolin and Its Metabolites in Mice. Journal of Agricultural and Food Chemistry, 70(16), 5026-5038.
Zhao, Y., Wang, P., & Sang, S. (2019). Dietary genistein inhibits methylglyoxal-induced advanced glycation end product formation in mice fed a high-fat diet. The Journal of Nutrition, 149(5), 776-787.
Zheng, J., Guo, H., Ou, J., Liu, P., Huang, C., Wang, M., et al. (2021). Benefits, deleterious effects and mitigation of methylglyoxal in foods: A critical review. Trends in Food Science & Technology, 107, 201-212.
Zhou, J., Ueda, K., Zhao, J., & Sparrow, J. R. (2015). Correlations between photodegradation of bisretinoid constituents of retina and dicarbonyl adduct deposition. Journal of Biological Chemistry, 290(45), 27215-27227.
Zunkel, K., Simm, A., & Bartling, B. (2020). Long-term intake of the reactive metabolite methylglyoxal is not toxic in mice. Food and Chemical Toxicology, 141,111333.