Medical Hypotheses 183 (2024) 111248

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Toxic advanced glycation end-products (TAGE) are major structures ofcytotoxic AGEs derived from glyceraldehyde
Masayoshi Takeuchi a, *, Hirokazu Suzuki b, Kenji Takeda a, Akiko Sakai-Sakasai aab

Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku Uchinada-machi, Ishikawa 920-0293, Japan
Department of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa 920-1181, JapanA R T I C L E I N F O

A B S T R A C T

Keywords:
Advanced glycation end-products (AGEs)
Glyceraldehyde (GA)GA-derived AGEs (GA-AGEs)
Toxic AGEs (TAGE)
Lifestyle-related diseases (LSRD)
1,4-dihydropyrazine

The habitual overconsumption of sugars has been implicated in the onset and/or development of lifestyle-relateddiseases (LSRD). Advanced glycation end-products (AGEs) have recently been proposed as one of the factors
contributing to LSRD. Therefore, strategies that reduce AGEs may be used to effectively prevent and treat LSRD.
AGE structures vary according to the types of reducing sugars/carbonyl compounds with which they react;
therefore, the AGE structure primarily responsible for LSRD remains unknown. Among the various AGEs pro­
duced in the human body, glyceraldehyde (GA)-derived AGEs (GA-AGEs) exert strong cytotoxic effects that
contribute to the onset/development of LSRD. The dysregulated metabolism of glucose/fructose associated withmodern diets promotes the binding of excessive GA generated in cells to intracellular proteins, which results inthe production and accumulation of GA-AGEs and, thus, many types of cellular damage. The toxic AGEs (TAGE)
theory originated from our findings. The hypothesis proposed herein is that strongly cytotoxic TAGE structuresare GA-derived 1,4-dihydropyrazine compounds, which differ from the known structures of GA-AGEs (i.e., GAderived pyridinium compound, trihydroxy-triosidine, and pyrrolopyridinium lysine dimer derived from GA).

Introduction
Since the content of sucrose/high-fructose corn syrup is very high insugar-sweetened beverages/processed foods, their habitual over­consumption is associated with the onset and/or development of obesity
and metabolic syndrome in addition to an increased risk of diabetes
mellitus (DM), nonalcoholic steatohepatitis (NASH), cardiovasculardiseases (CVD), Alzheimer’s disease (AD), and cancer [1–4]. However,
the mechanisms responsible remain unclear.
Under hyperglycemic conditions, advanced glycation end-products(AGEs) are generated through non-enzymatic glycation, also known as
the Maillard reaction, which occurs when the carbonyl group of
reducing sugars/carbonyl compounds reacts with the amino group ofamino acids/proteins [5,6]. The types of AGEs produced by this reaction
depend on the reducing sugars (i.e., glyceraldehyde (GA), glucose (Glu),and fructose (Fru)) and carbonyl compounds (i.e., methylglyoxal(MGO), glyoxal (GO), 3-deoxyglucosone (3-DG), and glycolaldehyde(Glycol)) involved [7–10]. AGEs were originally characterized by theemission of AGE-specific fluorescence and their ability to form crosslinks with and between amino acids (i.e., crosslines, pentosidine, andvesperlysines); however, compounds that do not form cross-links and/or
emit AGE-specific fluorescence, such as pyrraline, Nε-(carboxyethyl)
lysine (CEL), Nε-(carboxymethyl)lysine (CML), MGO-derived hydro­
imidazolone 1 (MG-H1), and argpyrimidine, are now considered to be
AGEs [5,6,11,12].
We recently demonstrated the involvement of the intracellularaccumulation of GA-AGEs derived from GA, a tricarbohydrate andmetabolic intermediate of glucose and fructose [13,14], in the onset
and/or development of lifestyle-related diseases (LSRD) through theinduction of damage in various cells [15–27]. The accumulation of GA-

Abbreviations: AD, Alzheimer’s disease; AGEs, advanced glycation end-products; Arg, arginine; CEL, Nε-(carboxyethyl)lysine; CML, Nε-(carboxymethyl)lysine;
CVD, cardiovascular diseases; 3-DG, 3-deoxyglucosone; DM, diabetes mellitus; DN-HD, diabetic nephropathy with hemodialysis; Fru, fructose; GA, glyceraldehyde;
GA-AGEs, GA-derived AGEs; GLAP, GA-derived pyridinium compound; Glu, glucose; Glycol, glycolaldehyde; GO, glyoxal; LSRD, lifestyle-related diseases; Lys, lysine;
MGO, methylglyoxal; MG-H1, MGO-derived hydroimidazolone 1; NASH, nonalcoholic steatohepatitis; PPG, pyrrolopyridinium lysine dimer derived from GA; R-NH2,ε-amino residue of Lys; RAGE, receptor for AGEs; TAGE, toxic AGEs.
* Corresponding author.
E-mail addresses: takeuchi@kanazawa-med.ac.jp (M. Takeuchi), h-suzuki@hokuriku-u.ac.jp (H. Suzuki), ktakeda@kanazawa-med.ac.jp (K. Takeda), asakasai@kanazawa-med.ac.jp (A. Sakai-Sakasai).
https://doi.org/10.1016/j.mehy.2023.111248
Received 28 September 2023; Received in revised form 13 November 2023; Accepted 6 December 2023
Available online 19 December 2023
0306-9877/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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Medical Hypotheses 183 (2024) 111248

Fig 1. Production pathway of glyceraldehyde-derived pyridinium/pyrrolopyridinium compounds. GA: glyceraldehyde, GLAP: GA-derived pyridinium compound,
PPG: pyrrolopyridinium lysine dimer derived from GA, R-NH2: ε-amino residue of lysine, B: base, [O]: oxidation.

derived 1,4-dihydropyrazine rings that emit AGE-specific fluorescenceand form intra/intermolecular cross-links as candidate TAGE structures.

AGEs has been implicated in the pathogenesis of NASH, CVD, DM and its
complications, some types of cancers, and AD [14,28–33]. Based on ourfindings, we proposed the toxic AGEs (TAGE) theory [14,28–33].
Furthermore, elevated blood TAGE levels induced by various types ofcellular damage may be a useful new biomarker for the early diagnosis,
treatment response monitoring, and prevention of the onset and/or
development of LSRD, such as DM [30–32]. In other words, it may bepossible to predict the onset/development of LSRD at an early stage bymeasuring TAGE levels in blood. This will further contribute to theprevention of LSRD and the extension of a healthy life expectancy.
Since AGE structures markedly vary in vivo and their production isdependent on complex reactions (such as dehydration, oxidation,condensation, and rearrangements), only the structures of a small
number of AGEs have been elucidated to date [5,6,11,12], while those ofhighly cytotoxic AGEs remain unknown. Four types of GA-AGE struc­tures have been identified using proteomic analyses [34]: GA-derived
pyridinium compound (GLAP) [35], trihydroxy-triosidine [36], MGH1 [37], and argpyrimidine [38]. GLAP and trihydroxy-triosidine
have been detected in the lysine (Lys) residues of proteins and MG-H1
and argpyrimidine in arginine (Arg) residues. A previous study
demonstrated that the glycation of Lys residues was more strongly
dependent on the dose of GA applied than that of Arg residues [34]. Thisfinding indicates that Lys residues are more likely to form GA-AGEs thanArg residues, which is important for both the prevention and treatmentof LSRD.

Evaluation of the hypothesis
A previous study identified seven AGE classes (Glu-/Fru-/GA-/Gly­col-/MGO-/GO-/3-DG-derived AGEs) and CML in human serum [7–10].
To examine the toxicity of GA-AGEs, we produced a specific anti-TAGE
antibody and showed that it bound to the epitopes of GA-AGE structures,
but not to AGEs with well-characterized pyrraline, CEL, CML, andpentosidine. Furthermore, the anti-TAGE antibody did not bind to AGEs
produced from reducing sugars/carbonyl compounds (such as imida­
zolones, MG-H1, argpyrimidine, and GO-/MGO-Lys dimers) (Suppl.
data) [8,41]. It also did not recognize AGEs with unknown structures,
including six AGE classes (Glu-/Fru-/Glycol-/MGO-/GO-/3-DG-AGEs)[7–10], or GA-AGE structures with pyridine rings as epitopes, including
GLAP and trihydroxy-triosidine.
Senavirathna et al. showed that the glycation of Lys residues in thepancreatic cancer cell line, PANC-1 increased in a GA dose-dependent
manner, whereas the number of Arg modifications did not [34]. Usui
& Hayase [35] and Tessier et al. [36] both proposed that the pyridinium
compounds, GLAP and trihydroxy-triosidine, respectively, are GA-AGEs.
The pathway to produce GLAP and trihydroxy-triosidine is shown in
Fig. 1. The initial Maillard reaction involves the formation of Schiffbases between the ε-amino residue of Lys (R-NH2) and the carbonyl
residue of GA, followed by the Amadori rearrangement reaction incompounds, which leads to the production of ketoamine (adduct 1). The
imino residue of ketoamine (adduct 1) adducts to the carbonyl residue ofGA and diketoamine is formed by dehydration. A diketoamine iscyclized by aldol condensation and isomerized to an intermediate. GLAP
is then produced from the intermediate by dehydration [42]. On theother hand, trihydroxy-triosidine is produced from the intermediate byoxidation [36].
Although GLAP/trihydroxy-triosidine, pyridinium-type AGEs, havebeen identified as GA-AGEs, the pathological implications of GA-AGEshave yet to be clarified. Shigeta et al. recently examined the Maillard
reaction between Nα-acetyl-L-Lys and GA under physiological conditions
and found that the main products were two novel fluorescent AGEs, GAderived pyrrolopyridinium Lys dimers (PPG1 and PPG2), in which
pyrrolopyridine ring structures crosslink two Lys molecules (see Fig. 1).
They suggested a mechanism for the formation of PPG1 and PPG2 in vitro
involving a unique reaction for skeleton expansion in addition to the

Hypothesis
GA-AGEs represent a structurally heterogeneous group of molecules;
however, the specific structures within this group that are responsible
for their toxicity remain unclear. Previous studies reported that additionof an anti-GA-AGEs antibody completely mitigated neurotoxicity
induced by serum AGEs in patients with diabetic nephropathy withhemodialysis (DN-HD), whereas similar effects were not observed with
antibodies targeting other types of AGEs or CML [39,40]. Therefore,
only AGE structures with epitopes that bind to the anti-GA-AGE anti­
body appear to be toxic. Accordingly, specific AGEs that bind to the antiGA-AGE antibody are referred to as TAGE, distinguishing them fromother AGEs and GA-AGEs, including GLAP, trihydroxy-triosidine, MGH1, and argpyrimidine. None of these structures exhibited the ability toform cross-links with or between amino acids and/or emitted AGEspecific fluorescence. We herein propose two compounds with GA2

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Medical Hypotheses 183 (2024) 111248

Fig 2. A proposed production pathway of candidate toxic AGE (TAGE) structures. R-NH2: ε-amino residue of lysine.

typical formation of Schiff bases [43].
The proposed pathway for the production of TAGE is shown in Fig. 2.
The initial reaction involves the formation of Schiff bases between RNH2 and GA, followed by the Amadori rearrangement reaction, whichleads to the production of adduct 1. In contrast to the production of
GLAP, trihydroxy-triosidine, and PPGs (see Fig. 1), the reaction of the
carbonyl residue of adduct 1 with R-NH2 and the Amadori rearrange­
ment reaction forms adduct 2. Adduct 3 is formed from adduct 2 via
similar reactions, which then forms adduct 4 by a reaction with GA. A
1,4-dihydropyrazine compound is formed from the intermediate by thecyclization of adduct 4 and dehydration (trimer structure; Route A). In
addition, adduct 1 reacts with R-NH2 to form adduct 5, which reacts
with the carbonyl residue of GA to form adduct 6 via the Amadori
rearrangement reaction. A 1,4-dihydropyrazine compound is formed by
the cyclization of adduct 6 and dehydration (dimer structure; Route B).

treatment response monitoring, and prevention of the onset and/or
development of LSRD, including DM and non-DM. Therefore, the onset
and/or development of LSRD may be predicted at an early stage bymeasuring serum TAGE levels. This will further contribute to the pre­vention of LSRD and the extension of a healthy life expectancy.
Collectively, our findings suggest the potential of serum TAGE levels as a
useful biomarker for not only the prevention/early diagnosis of LSRD,
but also evaluations of the efficacy of LSRD treatments [30–32]. In the
future, the identification of high-risk patients may be facilitated by theassessment of TAGE levels and important information may be obtained
to expedite treatment decision-making. However, there is currently noevidence to support a relationship between blood levels of GA-AGEs anddiseases using anti-GLAP, anti-trihydroxy-triosidine, and anti-PPGs
antibodies.
Conclusions

Consequences of the hypothesis and discussion

Among AGE subspecies, we demonstrated that GA-AGEs are pre­dominantly toxic and, thus, are referred to as TAGE. The anti-TAGE
antibody does not bind to GA-AGE structures with pyridine or pyrrolo­
pyridine rings as epitopes, such as GLAP, trihydroxy-triosidine, or PPGs.
Moreover, neither of these structures (GLAP and trihydroxy-triosidine)emit AGE-specific fluorescence or have the ability to form cross-links
with or between amino acids. We herein propose two compounds with
GA-derived 1,4-dihydropyrazine rings [PCT/JP2019/034195] thatpossess these properties as candidate TAGE structures (Fig. 2). The antiTAGE antibody recognized trimer (the final product of route A)/dimer(the final product of route B) bands as well as monomer bands (intra­
molecular protein cross-links) in a reaction mixture between egg lyso­
zyme proteins and GA (data not shown). The novel “TAGE theory”
provides new research perspectives into LSRD.

In our previous studies, we showed that serum AGE fractions frompatients with DN-HD were neurotoxic and this effect was neutralized by
the anti-TAGE antibody [39,40]. Based on these findings, cytotoxic GAAGE structures may be identified by binding to the anti-TAGE antibody.
AGEs that bind to the anti-TAGE antibody are referred to as TAGE,
which are toxic GA-AGEs [32,44]. We recently reported that intracel­lular TAGE molecules were cytotoxic in hepatocytes [15–18], neuro­
blastoma cells [19–21], pancreatic cancer cells [22], cardiomyocytes[23], cardiac fibroblasts [24], pancreatic β-cells [25], myoblast cells[26], and osteoblasts [27]. TAGE have been implicated in apoptotic
and/or necrotic events and, thus, cell death and tissue damage. The
extracellular leakage of cytotoxic TAGE has been suggested to increased
their concentration in circulating fluids [30–32]. Furthermore, extra­
cellular TAGE and receptor for AGEs (RAGE) interactions have beenshown to affect intracellular signaling, gene expression, and the releaseof proinflammatory molecules and also promote the production ofreactive oxygen species in many cell types [29–33], which collectively
contribute to the development of LSRD.
Elevated serum TAGE levels as a result of various types of cellular
damage have potential as a new biomarker for the early diagnosis,

Author contributions
All authors substantially contributed to the preparation of this article(M.T.: designed the manuscript, M.T. and H.S.: original and revised draft
preparation, editing, and visualization, K.T. and A.S.-S.: review). All
authors have read and agreed to the published version of the revised
3

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Medical Hypotheses 183 (2024) 111248

manuscript.

neurite outgrowth in SH-SY5Y human neuroblastoma cells. Nutrients 2020;12(10):2958. https://doi.org/10.3390/nu12102958.
[21] Ooi H, Nasu R, Furukawa A, Takeuchi M, Koriyama Y. Pyridoxamine andaminoguanidine attenuate the abnormal aggregation of β-tubulin and suppressionof neurite outgrowth by glyceraldehyde-derived toxic advanced glycation endproducts. Front Pharmacol 2022;13:921611. https.//doi.org/10.3389/
fphar.2022.921611.
[22] Takata T, Ueda T, Sakasai-Sakai A, Takeuchi M. Generation of glyceraldehydederived advanced glycation end-products in pancreatic cancer cells and thepotential of tumor promotion. World J Gastroenterol 2017;23(27):4910–9. https://doi.org/10.3748/wjg.v23.i27.4910.
[23] Takata T, Sakasai-Sakai A, Ueda T, Takeuchi M. Intracellular toxic advanced
glycation end-products in cardiomyocytes may cause cardiovascular disease. Sci
Rep 2019;9(1):2121. https://doi.org/10.1038/s41598-019-39202-5.
[24] Takata T, Sakasai-Sakai A, Takeuchi M. Intracellular toxic advanced glycation endproducts may induce cell death and suppress cardiac fibroblasts. Metabolites 2022;12(7):615. https://doi.org/10.3390/metabo12070615.
[25] Takata T, Sakasai-Sakai A, Takeuchi M. Intracellular toxic advanced glycation endproducts in 1.4E7 cell line induce death with reduction of microtubule-associatedprotein 1 light chain 3 and p62. Nutrients 2022;14(2):332. https://doi.org/
10.3390/nu14020332.
[26] Takata T, Sakasai-Sakai A, Takeuchi M. Impact of intracellular toxic advanced
glycation end-products (TAGE) on murine myoblast cell death. Diabetol Metab
Syndr 2020;12:54. https://doi.org/10.1186/s13098-020-00561-z.
[27] Sakasai-Sakai A, Takata T, Takeuchi M. The association between accumulation of
toxic advanced glycation end-products and cytotoxic effect in MC3T3-E1 cells.
Nutrients 2022;14(5):990. https://doi.org/10.3390/nu14050990.
[28] Takeuchi M, Yamagishi S. TAGE (toxic AGEs) hypothesis in various chronic
diseases. Med Hypotheses 2004;63(3):449–52. https://doi.org/10.1016/j.
mehy.2004.02.042.
[29] Takeuchi M, Takino J, Yamagishi S. Involvement of the toxic AGEs (TAGE)-RAGE
system in the pathogenesis of diabetic vascular complications: a novel therapeuticstrategy. Curr Drug Targets 2010;11(11):1468–82. https://doi.org/10.2174/
1389450111009011468.
[30] Takeuchi M. Serum levels of toxic AGEs (TAGE) may be a promising novel
biomarker for the onset/progression of lifestyle-related diseases. Diagnostics 2016;
6(2):23. https://doi.org/10.3390/diagnostics6020023.
[31] Takeuchi M. Toxic AGEs (TAGE) theory: A new concept for preventing thedevelopment of diseases related to lifestyle. Diabetol Metab Syndr 2020;12(1):105.
https://doi.org/10.1186/s13098-020-00614-3.
[32] Takeuchi M, Sakasai-Sakai A, Takata T, Takino J, Koriyama Y. Effects of toxic AGEs
(TAGE) on human health. Cells 2022;11(14):2178. https://doi.org/10.3390/
cells11142178.
[33] Sakasai-Sakai A, Takeda K, Takeuchi M. Involvement of intercellular TAGE and theTAGE-RAGE-ROS axis in the onset and progression of NAFLD/NASH. Antioxidants
2023;12(3):748. https://doi.org/10.3390/antiox12030748.
[34] Senavirathna L, Ma C, Chen R, Pan S. Proteomic investigation of glyceraldehydederived intracellular AGEs and their potential influence on pancreatic ductal cells.
Cells 2021;10(5):1005. https://doi.org/10.3390/cells10051005.
[35] Usui T, Hayase F. Isolation and identification of the 3-hydroxy-5-hydroxymethylpyridinium compound as a novel advanced glycation end product on
glyceraldehyde-related maillard reaction. Biosci Biotechnol Biochem 2003;67(4):930–2. https://doi.org/10.1271/bbb.67.930.
[36] Tessier FJ, Monnier VM, Sayre LM, Kornfield JA. Triosidines: novel maillard
reaction products and cross-links from the reaction of triose sugars with lysine andarginine residues. Biochem J 2003;369(Pt3):705–19. https://doi.org/10.1042/
BJ20020668.
[37] Usui T, Watanabe H, Hayase F. Isolation and identification of 5-methyl-imidazolin4-one derivative as glyceraldehyde-derived advanced glycation end product. Biosci
Biotechnol Biochem 2006;70(6):1496–8. https://doi.org/10.1271/bbb.50584.
[38] Usui T, Ohguchi M, Watanabe H, Hayase F. The formation of argpyrimidine inglyceraldehyde-related glycation. Biosci Biotechnol Biochem 2008;72(2):568–71.
https://doi.org/10.1271/bbb.70455.
[39] Takeuchi M, Bucala R, Suzuki T, Ohkubo T, Yamazaki M, Koike T, et al.
Neurotoxicity of advanced glycation end-products for cultured cortical neurons.
J Neuropathol Exp Neurol 2000;59(12):1094–105. https://doi.org/10.1093/jnen/
59.12.1094.
[40] Takeuchi M, Kikuchi S, Sasaki N, Suzuki T, Watai T, Iwaki M, et al. Involvement ofadvanced glycation end-products (AGEs) in Alzheimer’s disease. Curr Alzheimer
Res 2004;1(1):39–46. https://doi.org/10.2174/1567205043480582.
[41] Tahara N, Yamagishi S, Takeuchi M, Honda A, Tahara A, Nitta Y, et al. Positive
association between serum level of glyceraldehyde-derived advanced glycation end
products and vascular inflammation evaluated by [18F]fluorodeoxyglucose
positron emission tomography. Diabetes Care 2012;35(12):2618–25. https://doi.
org/10.2337/dc12-0087. (Supplementary data: https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC3507595/bin/supp_dc12-0087v120087_
DC120087SupplementaryData.pdf).
[42] Usui T, Shimohira K, Watanabe H, Hayase F. Detection and determination ofglyceraldehyde-derived pyridinium-type advanced glycation end product in

Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Financial support/Funding
This work was supported by JSPS KAKENHI Grant Number
JP21H04865.
References[1] Mucci L, Santilli F, Cuccurullo C, Davi G. Cardiovascular risk and dietary sugar
intake: is the link so sweet? Intern Emerg Med 2012;7(4):313–22. https://doi.org/
10.1007/s11739-011-0606-7.
[2] Imamura F, O’Connor L, Ye Z, Mursu J, Hayashino Y, Bhupathiraju SN, et al.
Consumption of sugar sweetened beverages, artificially sweetened beverages, andfruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, andestimation of population attributable fraction. Br J Sports Med 2016;50(8):496–504. https://doi.org/10.1136/bjsports-2016-h3576rep.
[3] Malik VS. Sugar sweetened beverages and cardiometabolic health. Curr Opin
Cardiol 2017;32(5):572–9. https://doi.org/10.1097/HCO.0000000000000439.
[4] Yki-Järvinen H, Luukkonen PK, Hodson L, Moore JB. Dietary carbohydrates andfats in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2021;18(11):
770–86. https://doi.org/10.1038/s41575-021-00472-y.
[5] Takeuchi M, Makita Z. Alternative routes for the formation of immunochemicallydistinct advanced glycation end-products in vivo. Curr Mol Med 2001;1(3):305–15.
https://doi.org/10.2174/1566524013363735.
[6] Poulsen MW, Hedegaard RV, Andersen JM, de Courten B, Bügel S, Nielsen J, et al.
Advanced glycation endproducts in food and their effects on health. FoodChem
Toxicol 2013;60:1037. https://doi.org/10.1016/j.fct.2013.06.052.
[7] Takeuchi M, Makita Z, Yanagisawa K, Kamaeda K, Koike T. Detection of
noncarboxymethyllysine and carboxymethyllysine advanced glycation end
products (AGE) in serum of diabetic patients. Mol Med 1999;5(6):393–405.
[8] Takeuchi M, Makita Z, Bucala R, Suzuki T, Koike T, Kameda Y. Immunologicalevidence that non-carboxymethyllysine advanced glycation end-products areproduced from short chain sugars and dicarbonyl compounds in vivo. Mol Med
2000;6(2):114–25.
[9] Takeuchi M, Yanase Y, Matsuura N, Yamagishi S, Kameda Y, Bucala R, et al.
Immunological detection of a novel advanced glycation end-product. Mol Med
2001;7(11):783–91.
[10] Takeuchi M, Iwaki M, Takino J, Shirai H, Kawakami M, Bucala R, et al.
Immunological detection of fructose-derived advanced glycation end-products. Lab
Invest 2010;90(7):1117–27. https://doi.org/10.1038/labinvest.2010.62.
[11] Brings S, Fleming T, Freichel M, Muckenthaler MU, Herzig S, Nawroth PP.
Dicarbonyls and advanced glycation end-products in the development of diabetic
complications and targets for intervention. Int J Mol Sci 2017;18(5):984. https://doi.org/10.3390/ijms18050984.
[12] Jud P, Sourij H. Therapeutic options to reduce advanced glycation end products inpatients with diabetes mellitus: a review. Diabetes Res Clin Pract 2019;148:54–63.
https://doi.org/10.1016/j.diabres.2018.11.016.
[13] Takeuchi M, Yamagishi S. Alternative routes for the formation of glyceraldehydederived AGEs (TAGE) in vivo. Med Hypotheses 2004;63(3):453–5. https://doi.org/
10.1016/j.mehy.2004.03.005.
[14] Takeuchi M, Sakasai-Sakai A, Takata T, Takino J, Koriyama Y, Kikuchi C, et al.
Intracellular toxic AGEs (TAGE) triggers numerous types of cell damage.
Biomolecules 2021;11(3):387. https://doi.org/10.3390/biom11030387.
[15] Takino J, Kobayashi Y, Takeuchi M. The formation of intracellular glyceraldehydederived advanced glycation end-products and cytotoxicity. J Gastroenterol 2010;45(6):646–55. https://doi.org/10.1007/s00535-009-0193-9.
[16] Sakasai-Sakai A, Takata T, Takino J, Takeuchi M. Impact of intracellularglyceraldehyde-derived advanced glycation end-products on human hepatocyte
cell death. Sci Rep 2017;7(1):14282. https://doi.org/10.1038/s41598-017-147113.
[17] Sakasai-Sakai A, Takata T, Takeuchi M. Intracellular toxic advanced glycation endproducts promote the production of reactive oxygen species in HepG2 cells. Int J
Mol Sci 2020;21(14):4861. https://doi.org/10.3390/ijms21144861.
[18] Kikuchi C, Sakasai-Sakai A, Okimura R, Tanaka H, Takata T, Takeuchi M, et al.
Accumulation of toxic advanced glycation end-products induces cytotoxicity andinflammation in hepatocyte-like cells differentiated from human induced
pluripotent stem cells. Biol Pharm Bull 2021;44(10):1399–402. https://doi.org/
10.1248/bpb.b21-00520.
[19] Koriyama Y, Furukawa A, Muramatsu M, Takino J, Takeuchi M. Glyceraldehyde
caused Alzheimer’s disease-like alterations in diagnostic marker levels in SH-SY5Y
human neuroblastoma cells. Sci Rep 2015;5:13313. https://doi.org/10.1038/
srep13313.
[20] Nasu R, Furukawa A, Suzuki K, Takeuchi M, Koriyama Y. The effect ofglyceraldehyde-derived advanced glycation end-products on β-tubulin-inhibited4M. Takeuchi et al.

Medical Hypotheses 183 (2024) 111248

streptozotocin-induced diabetic rats. Biosci Biotechnol Biochem 2007;71(2):442–8.
https://doi.org/10.1271/bbb.60497.
[43] Shigeta T, Sakamoto K, Yamamoto T. Glyceraldehyde-derived advanced glycation
end-products having pyrrolopyridinium-based crosslinks. Biochem Biophys Rep
2021;26:100963. https://doi.org/10.1016/j.bbrep.2021.100963.

[44] Twarda-Clapa A, Olczak A, Białkowska AM, Koziołkiewicz M. Advanced glycation
end-products (AGEs): formation, chemistry, classification, receptors, and diseases
related to AGEs. Cells 2022;11(8):1312. https://doi.org/10.3390/cells11081312.

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