{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T06:40:30Z","timestamp":1782801630620,"version":"3.54.5"},"reference-count":114,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,19]],"date-time":"2023-03-19T00:00:00Z","timestamp":1679184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["21K11583"],"award-info":[{"award-number":["21K11583"]}]},{"name":"JSPS KAKENHI","award":["21H04865"],"award-info":[{"award-number":["21H04865"]}]},{"name":"Hokkoku Foundation for Cancer Research","award":["21K11583"],"award-info":[{"award-number":["21K11583"]}]},{"name":"Hokkoku Foundation for Cancer Research","award":["21H04865"],"award-info":[{"award-number":["21H04865"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The repeated excessive intake of sugar, a factor that contributes to the onset of nonalcoholic fatty liver disease (NAFLD) and its progression to the chronic form of nonalcoholic steatohepatitis (NASH), markedly increases the hepatocyte content of glyceraldehyde (GA), a glucose\/fructose metabolic intermediate. Toxic advanced glycation end-products (toxic AGEs, TAGE) are synthesized by cross-linking reactions between the aldehyde group of GA and the amino group of proteins, and their accumulation has been implicated in the development of NAFLD\/NASH and hepatocellular carcinoma (HCC). Our previous findings not only showed that hepatocyte disorders were induced by the intracellular accumulation of TAGE, but they also indicated that extracellular leakage resulted in elevated TAGE concentrations in circulating fluids. Interactions between extracellular TAGE and receptor for AGEs (RAGE) affect intracellular signaling and reactive oxygen species (ROS) production, which may, in turn, contribute to the pathological changes observed in NAFLD\/NASH. RAGE plays a role in the effects of the extracellular leakage of TAGE on the surrounding cells, which ultimately promote the onset and progression of NAFLD\/NASH. This review describes the relationships between intracellular TAGE levels and hepatocyte and hepatic stellate cell (HSC) damage as well as the TAGE\u2013RAGE\u2013ROS axis in hepatocytes, HSC, and HCC cells. The \u201cTAGE theory\u201d will provide novel insights for future research on NAFLD\/NASH.<\/jats:p>","DOI":"10.3390\/antiox12030748","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T05:46:42Z","timestamp":1679291202000},"page":"748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Involvement of Intracellular TAGE and the TAGE\u2013RAGE\u2013ROS Axis in the Onset and Progression of NAFLD\/NASH"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1258-1725","authenticated-orcid":false,"given":"Akiko","family":"Sakasai-Sakai","sequence":"first","affiliation":[{"name":"Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0690-127X","authenticated-orcid":false,"given":"Kenji","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1057-3764","authenticated-orcid":false,"given":"Masayoshi","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.jhep.2018.10.033","article-title":"Non-alcoholic fatty liver disease\u2014A global public health perspective","volume":"70","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/j.metabol.2016.01.012","article-title":"Epidemiology and natural history of non-alcoholic fatty liver disease","volume":"65","author":"Fazel","year":"2016","journal-title":"Metabolism"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease\u2014Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1111\/apt.17158","article-title":"Review article: The epidemiologic burden of non-alcoholic fatty liver disease across the world","volume":"56","author":"Henry","year":"2022","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1002\/hep.27376","article-title":"Liver sinusoidal endothelial cells in hepatic fibrosis","volume":"61","author":"Deleve","year":"2015","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"305","DOI":"10.2174\/1566524013363735","article-title":"Alternative routes for the formation of immunochemically distinct advanced glycation end-products in vivo","volume":"1","author":"Takeuchi","year":"2001","journal-title":"Curr. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.fct.2013.06.052","article-title":"Advanced glycation endproducts in food and their effects on health","volume":"60","author":"Poulsen","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1007\/s00535-009-0193-9","article-title":"The formation of intracellular glyceraldehyde-derived advanced glycation end-products and cytotoxicity","volume":"45","author":"Takino","year":"2010","journal-title":"J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14282","DOI":"10.1038\/s41598-017-14711-3","article-title":"Impact of intracellular glyceraldehyde-derived advanced glycation end-products on human hepatocyte cell death","volume":"7","author":"Takata","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sakasai-Sakai, A., Takata, T., and Takeuchi, M. (2020). Intracellular toxic advanced glycation end-products promote the production of reactive oxygen species in HepG2 cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21144861"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1248\/bpb.b21-00520","article-title":"Accumulation of toxic advanced glycation end-products induces cytotoxicity and inflammation in hepatocyte-like cells differentiated from human induced pluripotent stem cells","volume":"44","author":"Kikuchi","year":"2021","journal-title":"Biol. Pharm. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13313","DOI":"10.1038\/srep13313","article-title":"Glyceraldehyde caused Alzheimer\u2019s disease-like alterations in diagnostic marker levels in SH-SY5Y human neuroblastoma cells","volume":"5","author":"Koriyama","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4910","DOI":"10.3748\/wjg.v23.i27.4910","article-title":"Generation of glyceraldehyde-derived advanced glycation end-products in pancreatic cancer cells and the potential of tumor promotion","volume":"23","author":"Takata","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1038\/s41598-019-39202-5","article-title":"Intracellular toxic advanced glycation end-products in cardiomyocytes may cause cardiovascular disease","volume":"9","author":"Takata","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13098-020-00561-z","article-title":"Impact of intracellular toxic advanced glycation end-products (TAGE) on murine myoblast cell death","volume":"12","author":"Takata","year":"2020","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Takata, T., Sakasai-Sakai, A., and Takeuchi, M. (2022). Intracellular toxic advanced glycation end-products in 1.4E7 cell line induce death with reduction of microtubule-associated protein 1 light chain 3 and p62. Nutrients, 14.","DOI":"10.3390\/nu14020332"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sakasai-Sakai, A., Takata, T., and Takeuchi, M. (2022). The association between accumulation of toxic advanced glycation end-products and cytotoxic effect in MC3T3-E1 cells. Nutrients, 14.","DOI":"10.3390\/nu14050990"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Takata, T., Sakasai-Sakai, A., and Takeuchi, M. (2022). Intracellular toxic advanced glycation end-products may induce cell death and suppress cardiac fibroblasts. Metabolites, 12.","DOI":"10.3390\/metabo12070615"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Takeuchi, M. (2016). Serum levels of toxic AGEs (TAGE) may be a promising novel biomarker for the onset\/progression of lifestyle-related diseases. Diagnostics, 6.","DOI":"10.3390\/diagnostics6020023"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s13098-020-00614-3","article-title":"Toxic AGEs (TAGE) theory: A new concept for preventing the development of diseases related to lifestyle","volume":"12","author":"Takeuchi","year":"2020","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Takeuchi, M., Sakasai-Sakai, A., Takata, T., Takino, J., and Koriyama, Y. (2022). Effects of toxic AGEs (TAGE) on human health. Cells, 11.","DOI":"10.3390\/cells11142178"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"845","DOI":"10.3233\/JAD-2009-0974","article-title":"Involvement of toxic AGEs (TAGE) in the pathogenesis of diabetic vascular complications and Alzheimer\u2019s disease","volume":"16","author":"Takeuchi","year":"2009","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.2174\/1389450111009011468","article-title":"Involvement of the toxic AGEs (TAGE)-RAGE system in the pathogenesis of diabetic vascular complications: A novel therapeutic strategy","volume":"11","author":"Takeuchi","year":"2010","journal-title":"Curr. Drug Targets"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"880","DOI":"10.4254\/wjh.v6.i12.880","article-title":"Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies","volume":"6","author":"Takeuchi","year":"2014","journal-title":"World J. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Takeuchi, M., Takino, J., Sakasai-Sakai, A., Takata, T., and Tsutsumi, M. (2017). Toxic AGE (TAGE) theory for the pathophysiology of the onset\/progression of NAFLD and ALD. Nutrients, 9.","DOI":"10.3390\/nu9060634"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Takeuchi, M., Sakasai-Sakai, A., Takata, T., Takino, J., Koriyama, Y., Kikuchi, C., Furukawa, A., Nagamine, K., Hori, T., and Matsunaga, T. (2021). Intracellular toxic AGEs (TAGE) triggers numerous types of cell damage. Biomolecules, 11.","DOI":"10.3390\/biom11030387"},{"key":"ref_28","first-page":"2","article-title":"Assessment of total sugar and glucose concentrations in commonly consumed beverages in Japan","volume":"1","author":"Takeuchi","year":"2015","journal-title":"Nutr. Food Technol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Takeuchi, M., Takino, J., Furuno, S., Shirai, H., Kawakami, M., Muramatsu, M., Kobayashi, Y., and Yamagishi, S. (2015). Assessment of the concentrations of various advanced glycation end-products in beverages and foods that are commonly consumed in Japan. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118652"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1136\/bjsports-2016-h3576rep","article-title":"Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: Systematic review, meta-analysis, and estimation of population attributable fraction","volume":"50","author":"Imamura","year":"2016","journal-title":"Br. J. Sports Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s10654-017-0246-y","article-title":"Food groups and risk of type 2 diabetes mellitus: A systematic review and meta-analysis of prospective studies","volume":"32","author":"Schwingshackl","year":"2017","journal-title":"Eur. J. Epidemiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1097\/HCO.0000000000000439","article-title":"Sugar sweetened beverages and cardiometabolic health","volume":"32","author":"Malik","year":"2017","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41575-021-00472-y","article-title":"Dietary carbohydrates and fats in nonalcoholic fatty liver disease","volume":"18","author":"Luukkonen","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Patel, R., Baker, S.S., Liu, W., Desai, S., Alkhouri, R., Kozielski, R., Mastrandrea, L., Sarfraz, A., Cai, W., and Vlassara, H. (2012). Effect of dietary advanced glycation end products on mouse liver. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035143"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/BF03402128","article-title":"Detection of noncarboxymethyllysine and carboxymethyllysine advanced glycation end products (AGE) in serum of diabetic patients","volume":"5","author":"Takeuchi","year":"1999","journal-title":"Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1007\/BF03401779","article-title":"Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo","volume":"6","author":"Takeuchi","year":"2000","journal-title":"Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/BF03401969","article-title":"Immunological detection of a novel advanced glycation end-product","volume":"7","author":"Takeuchi","year":"2001","journal-title":"Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/labinvest.2010.62","article-title":"Immunological detection of fructose-derived advanced glycation end-products","volume":"90","author":"Takeuchi","year":"2010","journal-title":"Lab. Invest"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1093\/jnen\/59.12.1094","article-title":"Neurotoxicity of advanced glycation end-products for cultured cortical neurons","volume":"59","author":"Takeuchi","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.mehy.2004.02.042","article-title":"TAGE (toxic AGEs) hypothesis in various chronic diseases","volume":"63","author":"Takeuchi","year":"2004","journal-title":"Med. Hypotheses"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.2337\/dc12-0087","article-title":"Positive association between serum level of glyceraldehyde-derived advanced glycation end products and vascular inflammation evaluated by [18F] fluorodeoxyglucose positron emission tomography","volume":"35","author":"Tahara","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1271\/bbb.67.930","article-title":"Isolation and identification of the 3-hydroxy-5-hydroxymethyl-pyridinium compound as a novel advanced glycation end product on glyceraldehyde-related Maillard reaction","volume":"67","author":"Usui","year":"2003","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1042\/bj20020668","article-title":"Triosidines: Novel Maillard reaction products and cross-links from the reaction of triose sugars with lysine and arginine residues","volume":"369","author":"Tessier","year":"2003","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1271\/bbb.50584","article-title":"Isolation and identification of 5-methyl-imidazolin-4-one derivative as glyceraldehyde-derived advanced glycation end product","volume":"70","author":"Usui","year":"2006","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2174\/1567205043480582","article-title":"Involvement of advanced glycation end-products (AGEs) in Alzheimer\u2019s disease","volume":"1","author":"Takeuchi","year":"2004","journal-title":"Curr. Alzheimer Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Litwinowicz, K., Waszczuk, E., and Gamian, A. (2021). Advanced glycation end-products in common non-infectious liver diseases: Systematic review and meta-analysis. Nutrients, 13.","DOI":"10.3390\/nu13103370"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Twarda-Clapa, A., Olczak, A., Bia\u0142kowska, A.M., and Kozio\u0142kiewicz, M. (2022). Advanced glycation end-products (AGEs): Formation, chemistry, classification, receptors, and diseases related to AGEs. Cells, 11.","DOI":"10.3390\/cells11081312"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.mehy.2004.03.005","article-title":"Alternative routes for the formation of glyceraldehyde-derived AGEs (TAGE) in vivo","volume":"63","author":"Takeuchi","year":"2004","journal-title":"Med. Hypotheses"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0074-7742(02)50082-9","article-title":"Polyol pathway and diabetic peripheral neuropathy","volume":"50","author":"Oates","year":"2002","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1042\/bj2300053","article-title":"The purification and properties of human liver ketohexokinase. A role for ketohexokinase and fructose-bisphosphate aldolase in the metabolic production of oxalate from xylitol","volume":"230","author":"Bais","year":"1985","journal-title":"Biochem. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"166425","DOI":"10.1016\/j.bbadis.2022.166425","article-title":"Immunometabolism and the modulation of immune responses and host defense: A role for methylglyoxal?","volume":"1868","author":"Zhang","year":"2022","journal-title":"Biochim. Biophys. Acta\u2013Mol. Basis Dis."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Malinsk\u00e1, H., H\u00fcttl, M., Mikl\u00e1nkov\u00e1, D., Trnovsk\u00e1, J., Zapletalov\u00e1, I., Poruba, M., and Markov\u00e1, I. (2021). Ovariectomy-induced hepatic lipid and cytochrome P450 dysmetabolism precedes serum dyslipidemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094527"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1021\/acs.chemrestox.2c00160","article-title":"Methylglyoxal and its adducts: Induction, repair, and association with disease","volume":"35","author":"Lai","year":"2022","journal-title":"Chem. Res. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Takata, T., Sakasai-Sakai, A., Takino, J., and Takeuchi, M. (2019). Evidence for toxic advanced glycation end-products generated in the normal rat liver. Nutrients, 11.","DOI":"10.3390\/nu11071612"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Inoue, S., Takata, T., Nakazawa, Y., Nakamura, Y., Guo, X., Yamada, S., Ishigaki, Y., Takeuchi, M., and Miyazawa, K. (2021). Potential of an interorgan network mediated by toxic advanced glycation end-products in a rat model. Nutrients, 13.","DOI":"10.3390\/nu13010080"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"14987","DOI":"10.1016\/S0021-9258(18)42137-0","article-title":"Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface","volume":"267","author":"Schmidt","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1172\/JCI11771","article-title":"Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice","volume":"108","author":"Yamamoto","year":"2001","journal-title":"J. Clin. Invest"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s10719-020-09956-6","article-title":"Glycation reaction and the role of the receptor for advanced glycation end-products in immunity and social behavior","volume":"38","author":"Leerach","year":"2021","journal-title":"Glycoconj. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.tibs.2011.08.008","article-title":"RAGE: A single receptor fits multiple ligands","volume":"36","author":"Fritz","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.vph.2012.06.004","article-title":"The diverse ligand repertoire of the receptor for advanced glycation endproducts and pathways to the complications of diabetes","volume":"57","author":"Ramasamy","year":"2012","journal-title":"Vascul. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.bbamcr.2012.10.021","article-title":"RAGE in tissue homeostasis, repair and regeneration","volume":"1833","author":"Sorci","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"940","DOI":"10.2174\/138161208784139765","article-title":"AGE-RAGE system and carcinogenesis","volume":"14","author":"Abe","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"969","DOI":"10.2174\/138161208784139701","article-title":"Advanced glycation end products (AGEs) and their involvement in liver disease","volume":"14","author":"Hyogo","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1002\/lt.22306","article-title":"What is the role of the receptor for advanced glycation end products-ligand axis in liver injury?","volume":"17","author":"Basta","year":"2011","journal-title":"Liver Transplant."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1042\/bj20021371","article-title":"Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury","volume":"370","author":"Yonekura","year":"2003","journal-title":"Biochem J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/j.diabres.2007.01.030","article-title":"Short-chain aldehyde-derived ligands for RAGE and their actions on endothelial cells","volume":"77","author":"Yamamoto","year":"2007","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"20213","DOI":"10.1074\/jbc.M602110200","article-title":"Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression","volume":"281","author":"Yamagishi","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.3748\/wjg.v18.i15.1781","article-title":"Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression","volume":"18","author":"Takino","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.4254\/wjh.v7.i23.2459","article-title":"Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma","volume":"7","author":"Takino","year":"2015","journal-title":"World J. Hepatol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14090","DOI":"10.1038\/srep14090","article-title":"Role of Src in vascular hyperpermeability induced by advanced glycation end products","volume":"5","author":"Zhang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1038\/s41598-021-82619-0","article-title":"RasGRP2 inhibits glyceraldehyde-derived toxic advanced glycation end-products from inducing permeability in vascular endothelial cells","volume":"11","author":"Takino","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/dmrr.233","article-title":"The AGE-receptor in the pathogenesis of diabetic complications","volume":"17","author":"Vlassara","year":"2001","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1152\/ajpcell.00350.2007","article-title":"AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation","volume":"294","author":"Cai","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1111\/j.1440-1746.2007.04943.x","article-title":"Elevated levels of serum advanced glycation end products in patients with non-alcoholic steatohepatitis","volume":"22","author":"Hyogo","year":"2007","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1007\/s00535-010-0203-y","article-title":"Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: Clinical usefulness of AGEs as a biomarker for the attenuation of NASH","volume":"45","author":"Kimura","year":"2010","journal-title":"J. Gastroenterol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1002\/jcla.21797","article-title":"Elevation of serum levels of advanced glycation end products in patients with non-B or non-C hepatocellular carcinoma","volume":"29","author":"Kan","year":"2015","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/j.metabol.2006.05.007","article-title":"Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects","volume":"55","author":"Yamagishi","year":"2006","journal-title":"Metabolism."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.ijcard.2012.05.015","article-title":"Adiponectin is inversely associated with ratio of serum levels of AGEs to sRAGE and vascular inflammation","volume":"158","author":"Tahara","year":"2012","journal-title":"Int. J. Cardiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2337\/dc14-1435","article-title":"Ratio of serum levels of AGEs to soluble form of RAGE is a predictor of endothelial function","volume":"38","author":"Kajikawa","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.mvr.2007.09.004","article-title":"Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes","volume":"76","author":"Nakamura","year":"2008","journal-title":"Microvasc. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/dmrr.766","article-title":"Circulating advanced glycation end products (AGEs) and soluble form of receptor for AGEs (sRAGE) are independent determinants of serum monocyte chemoattractant protein-1 (MCP-1) levels in patients with type 2 diabetes","volume":"24","author":"Nakamura","year":"2008","journal-title":"Diabetes. Metab. Res. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.3748\/wjg.v21.i6.1784","article-title":"In vitro identification of nonalcoholic fatty liver disease-related protein hnRNPM","volume":"21","author":"Takino","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"87","DOI":"10.4236\/ajmb.2017.72007","article-title":"Gene expression changes associated with the loss of heterogeneous nuclear ribonucleoprotein M function","volume":"7","author":"Takino","year":"2017","journal-title":"Am. J. Mol. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Sakasai-Sakai, A., Takata, T., Takino, J., and Takeuchi, M. (2019). The relevance of toxic AGEs (TAGE) cytotoxicity to NASH pathogenesis: A mini-review. Nutrients, 11.","DOI":"10.3390\/nu11020462"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Shojaie, L., Iorga, A., and Dara, L. (2020). Cell death in liver diseases: A review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249682"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.4161\/auto.26448","article-title":"HSPA8\/HSC70 chaperone protein: Structure, function, and chemical targeting","volume":"9","author":"Stricher","year":"2013","journal-title":"Autophagy"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"a008656","DOI":"10.1101\/cshperspect.a008656","article-title":"Caspase functions in cell death and disease","volume":"5","author":"McIlwain","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"595371","DOI":"10.3389\/fmed.2021.595371","article-title":"Oxidative stress in non-alcoholic fatty liver disease. An updated mini review","volume":"8","author":"Marciano","year":"2021","journal-title":"Front. Med."},{"key":"ref_90","first-page":"9372182","article-title":"Activators and inhibitors of NRF2: A review of their potential for clinical development","volume":"2019","author":"Manda","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.freeradbiomed.2009.11.007","article-title":"Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis","volume":"48","author":"Chowdhry","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.jhep.2004.11.040","article-title":"Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients","volume":"42","author":"Malaguarnera","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5029414","DOI":"10.1155\/2016\/5029414","article-title":"A high-fat, high-fructose diet induces antioxidant imbalance and increases the risk and progression of nonalcoholic fatty liver disease in mice","volume":"2016","author":"Jarukamjorn","year":"2016","journal-title":"Scientifica"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1159\/000354461","article-title":"Angiotensin II induces C-reactive protein expression via AT1-ROS-MAPK-NF-\u03baB signal pathway in hepatocytes","volume":"32","author":"Zhao","year":"2013","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.1016\/j.febslet.2006.04.050","article-title":"Pigment epithelium- derived factor (PEDF) inhibits advanced glycation end product (AGE)-induced C-reactive protein expression in hepatoma cells by suppressing Rac-1 activation","volume":"580","author":"Yoshida","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/oby.2008.601","article-title":"Liver NF-\u03baB and AP-1 DNA binding in obese patients","volume":"17","author":"Videla","year":"2009","journal-title":"Obesity"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1053\/j.gastro.2015.04.009","article-title":"Hepatocyte nicotinamide adenine dinucleotide phosphate reduced oxidase 4 regulates stress signaling, fibrosis, and insulin sensitivity during development of steatohepatitis in mice","volume":"149","author":"Bettaieb","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Nasiri-Ansari, N., Androutsakos, T., Flessa, C.M., Kyrou, I., Siasos, G., Randeva, H., Kassi, E., and Papavassiliou, A.G. (2022). Endothelial cell dysfunction and nonalcoholic fatty liver disease (NAFLD): A concise review. Cells, 11.","DOI":"10.3390\/cells11162511"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.mvr.2007.05.001","article-title":"Olmesartan blocks advanced glycation end products (AGEs)-induced angiogenesis in vitro by suppressing receptor for AGEs (RAGE) expression","volume":"75","author":"Yamagishi","year":"2008","journal-title":"Microvasc. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.jstrokecerebrovasdis.2010.09.002","article-title":"Advanced glycation end products increase permeability of brain microvascular endothelial cells through reactive oxygen species-induced vascular endothelial growth factor expression","volume":"21","author":"Niiya","year":"2012","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1007\/s00125-002-1013-4","article-title":"Pigment epithelium-derived factor prevents advanced glycation end products-induced monocyte chemoattractant protein-1 production in microvascular endothelial cells by suppressing intracellular reactive oxygen species generation","volume":"46","author":"Inagaki","year":"2003","journal-title":"Diabetologia"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.brainres.2006.06.038","article-title":"Susceptibility of brain microvascular endothelial cells to advanced glycation end products-induced tissue factor upregulation is associated with intracellular reactive oxygen species","volume":"1108","author":"Niiya","year":"2006","journal-title":"Brain Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1159\/000111152","article-title":"Olmesartan blocks inflammatory reactions in endothelial cells evoked by advanced glycation end products by suppressing generation of reactive oxygen species","volume":"40","author":"Yamagishi","year":"2008","journal-title":"Ophthalmic Res."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Baiocchini, A., Montaldo, C., Conigliaro, A., Grimaldi, A., Correani, V., Mura, F., Ciccosanti, F., Rotiroti, N., Brenna, A., and Montalbano, M. (2016). Extracellular matrix molecular remodeling in human liver fibrosis evolution. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151736"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1007\/s00535-007-2152-7","article-title":"Advanced glycation end products enhance the proliferation and activation of hepatic stellate cells","volume":"43","author":"Iwamoto","year":"2008","journal-title":"J. Gastroenterol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1248\/bpb.b20-00708","article-title":"Suppression of hepatic stellate cell death by toxic advanced glycation end-products","volume":"44","author":"Takino","year":"2021","journal-title":"Biol. Pharm. Bull."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1002\/hep.510280111","article-title":"Expression of vascular endothelial growth factor in human hepatocellular carcinoma","volume":"28","author":"Yamaguchi","year":"1998","journal-title":"Hepatology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s00394-008-0753-4","article-title":"Effects of high-AGE beverage on RAGE and VEGF expressions in the liver and kidneys","volume":"48","author":"Sato","year":"2009","journal-title":"Eur. J. Nutr."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1096\/fj.02-0030fje","article-title":"Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin","volume":"16","author":"Okamoto","year":"2002","journal-title":"FASEB J."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1055\/s-2007-970425","article-title":"Pigment epithelium-derived factor (PEDF) blocks advanced glycation end product (AGE)-induced angiogenesis in vitro","volume":"39","author":"Yamagishi","year":"2007","journal-title":"Horm. Metab. Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/1475-2840-13-60","article-title":"Advanced glycation end products potentiate citrated plasma-evoked oxidative and inflammatory reactions in endothelial cells by up-regulating protease-activated receptor-1 expression","volume":"13","author":"Ishibashi","year":"2014","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3085756","DOI":"10.1155\/2019\/3085756","article-title":"Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in aging and age-related diseases","volume":"2019","author":"Moldogazieva","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1002\/jcp.30632","article-title":"d-Galactose induced early aging in human erythrocytes: Role of band 3 protein","volume":"237","author":"Remigante","year":"2022","journal-title":"J. Cell. Physiol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/3\/748\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:58:36Z","timestamp":1760122716000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/3\/748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,19]]},"references-count":114,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["antiox12030748"],"URL":"https:\/\/doi.org\/10.3390\/antiox12030748","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,19]]}}}