Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury

In the paper

“However, under pathological conditions, RAGEs can be upregulated and participate in various aging-related pathophysiologies, such as adult-onset type 2 diabetes mellitus (DM), cardiovascular disorders, myocardial infarction, chronic kidney failure, pancreatitis, cancer, Alzheimer’s disease (AD), Parkinson’s disease (PD), hepatic fibrosis, and alcohol-mediated tissue injury37,38.”

What the sources say

• Supported

  In “Potential factors underlying AGE-mediated effects on neurodegeneration” (page unavailable), the paper reports that AGE-albumin triggers RAGE generation on cell membranes and that RAGE-mediated signaling is upregulated in a rat model of neurotoxicity. The RAGE pathway section (page unavailable) also links RAGE activity to inflammation, tissue injury, and diabetic complications, supporting the claim that RAGE can participate in age-related pathology. (LLM, conf=0.89)

  cites [37] Chaudhuri, J. et al. The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality. Cell Metab. 28, 337–352 (2018). source
• Not checked yetcites [38] Wautier, M.-P., Guillausseau, P.-J. & Wautier, J.-L. Activation of the receptor for advanced glycation end products and consequences on health. Diabetes Metab. Syndrome: Clin. Res. Rev. 11, 305–309 (2017). source

In the paper

“Interactions between acetaldehyde or MDA and cellular proteins lead to the formation of MAA adducts, which are highly stable and resistant to rapid degradation178,179.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain

  “Increased levels of MAA adducts from alcohol exposure stimulate protein dysfunction and immune-induced tissue injury through interactions with Toll-like receptor-3 (TLR-3), TLR-6, calpain, collagen alpha-1 (XII) chain, procollagen type XIV alpha-1, protocadherin beta, or complement component proteins167,180.”

What the sources say

• Not checked yetcites [178] Tuma, D. J., Thiele, G. M., Xu, D., Klassen, L. W. & Sorrell, M. F. Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration. Hepatology 23, 872–880 (1996). source
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [179] McCaskill, M. L. et al. Hybrid malondialdehyde and acetaldehyde protein adducts form in the lungs of mice exposed to alcohol and cigarette smoke. Alcohol. Clin. Exp. Res. 35, 1106–1113 (2011). source
• Not checked yetcites [167] Tuma, D. J. & Casey, C. A. Dangerous byproducts of alcohol breakdown–focus on adducts. Alcohol Res. Health. 27, 285–290 (2003).
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [180] Patel, V. B., Worrall, S., Emery, P. W. & Preedy, V. R. Protein adduct species in muscle and liver of rats following acute ethanol administration. Alcohol Alcohol. 40, 485–493 (2005). sourceExperimental — accuracy not yet measured

In the paper

“These foods are rich in polyphenols such as gallic acid, flavonoids, anthocyanin, and ferulic acid, which attenuate protein glycation and prevent the biosynthesis of AGEs265–270.”

What the sources say

• Not checked yetcites [265] Premakumara, G. A. S., Abeysekera, W. K. S. M., Ratnasooriya, W. D., Chandrasekharan, N. V. & Bentota, A. P. Antioxidant, anti-amylase and anti-glycation potential of brans of some Sri Lankan traditional and improved rice (Oryza sativa L.) varieties. J. Cereal Sci. 58, 451–456 (2013). source
• Not checked yetcites [266] Dearlove, R. P., Greenspan, P., Hartle, D. K., Swanson, R. B. & Hargrove, J. L. Inhibition of protein glycation by extracts of culinary herbs and spices. J. Med. Food 11, 275–281 (2008). source
• Partly supported

  Section 7.1 reports that gallic and ferulic acids reduced AGE production in experimental systems, while Section 7.4 describes antiglycation and AGE-inhibiting effects of several flavonoids. The Introduction also says polyphenols can inhibit AGE biosynthesis. Our copy does not specifically establish an antiglycation effect for anthocyanin, so the full list is not supported. (LLM, conf=0.85)

  cites [267] Yeh, W. J., Hsia, S. M., Lee, W. H. & Wu, C. H. Polyphenols with antiglycation activity and mechanisms of action: a review of recent findings. J. Food Drug Anal. 25, 84–92 (2017). sourceExperimental — accuracy not yet measured
• Not checked yetcites [268] Chen, H., Virk, M. S. & Chen, F. Phenolic acids inhibit the formation of advanced glycation end products in food simulation systems depending on their reducing powers and structures. Int. J. Food Sci. Nutr. 67, 400–411 (2016). source
• Not checked yetcites [269] Ma, H. et al. Evaluation of polyphenol anthocyanin-enriched extracts of blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry for free radical scavenging, reactive carbonyl species trapping, anti-glycation, anti-β-amyloid aggregation, and microglial neuroprotective effects. Int. J. Mol. Sci. 19, 1–19 (2018). source
• Not checked yetcites [270] Daiponmak, W., Senakun, C. & Siriamornpun, S. Antiglycation capacity and antioxidant activities of different pigmented Thai rice. Int. J. Food Sci. Technol. 49, 1805–1810 (2014). source

In the paper

“Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage.”

What the sources say

• Not checked yetcites [6] Jamal, M. et al. in Neuroscience of Alcohol (ed Victor R. Preedy) 39–46 (Academic Press, 2019).
• Not checked yetcites [7] NIAAA. Alcohol Facts and Statistics. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) https://www.niaaa.nih.gov/sites/default/files/AlcoholFactsAndStats.pdf (2020).

In the paper

“For example, persistently high blood glucose, often observed in people with type 2 diabetes, increases the reservoir of substrate for accelerating AGE formation and activates protein kinase C and NADPH oxidases, producing ROS13,18.”

What the sources say

• Not checked yetcites [13] Peppa, M., Uribarri, J. & Vlassara, H. Glucose, advanced glycation end products, and diabetes complications: what is new and what works. Clin. Diabetes 21, 186 (2003). source
• Not checked yetcites [18] Yan, S. F., Ramasamy, R. & Schmidt, A. M. Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat. Clin. Pract. Endocrinol. Metab. 4, 285–293 (2008). source

In the paper

“Additionally, elevated oxidative stress can act as a catalyst to stimulate AGE accumulation, while activation of AGEs can increase oxidative stress, creating a synergistic feed-forward loop to accelerate pathophysiological conditions2–4.”

What the sources say

• Not checked yetcites [2] Henning, C. & Glomb, M. A. Pathways of the Maillard reaction under physiological conditions. Glycoconj. J. 33, 499–512 (2016). source
• Not checked yetcites [3] Uribarri, J. et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J. Gerontol. A Biol. Sci. Med Sci. 62, 427–433 (2007). source
• Not checked yetcites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source

In the paper

“Exogenous AGEs include dietary AGEs (e.g., foods and beverages such as soft drinks containing high fructose corn sirup and/or sugar) and cigarette smoke.”

What the sources say

• Not checked yetcites [5] Abate, G., Marziano, M., Rungratanawanich, W., Memo, M. & Uberti, D. Nutrition and AGE-ing: focusing on Alzheimer’s disease. Oxid. Med. Cell. Longev. 2017, 1–10 (2017). source
• Not checked yetcites [19] Luevano-Contreras, C. & Chapman-Novakofski, K. Dietary advanced glycation end products and aging. Nutrients 2, 1247–1265 (2010). source

In the paper

“These factors include excessive and/or prolonged alcohol consumption, cigarette smoking, the intake of high fat/caloric diets and/or extensively processed food, renal status, homeostatic imbalance, inflammation, hyperglycemia, and oxidative stress2–4.”

What the sources say

• Not checked yetcites [2] Henning, C. & Glomb, M. A. Pathways of the Maillard reaction under physiological conditions. Glycoconj. J. 33, 499–512 (2016). source
• Not checked yetcites [3] Uribarri, J. et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J. Gerontol. A Biol. Sci. Med Sci. 62, 427–433 (2007). source
• Not checked yetcites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source

In the paper

“In addition to dietary AGEs, cigarette smoke is found to contain reactive glycation products, which can increase AGE accumulation in the tissues and circulating blood of smokers23.”

What the sources say

• Not checked yetcites [23] Cerami, C. et al. Tobacco smoke is a source of toxic reactive glycation products. Proc. Natl Acad. Sci. USA 94, 13915–13920 (1997). source

In the paper

“In addition to long-lived proteins, AGEs can bind to proteins with short half-lives such as serum albumin, thereby activating RAGEs and inducing inflammatory responses followed by protein dysfunction and cell damage34.”

What the sources say

• Not checked yetcites [34] Rondeau, P. & Bourdon, E. The glycation of albumin: structural and functional impacts. Biochimie 93, 645–658 (2011). source

In the paper

“A RAGE is a multiligand cell surface receptor in the immunoglobulin superfamily35.”

What the sources say

• Not checked yetcites [35] Sessa, L. et al. The receptor for advanced glycation end-products (RAGE) is only present in mammals, and belongs to a family of cell adhesion molecules (CAMs). PloS One 9, e86903 (2014). source

In the paper

“AGEs also stimulate mitochondrial ROS production and c-Jun N-terminal protein kinase (JNK) and NADPH oxidase activity to induce mitochondrial dysfunction and oxidative stress51–53.”

What the sources say

• Not checked yetcites [51] Sergi, D. et al. Mitochondrial (Dys)function and insulin resistance: from pathophysiological molecular mechanisms to the impact of diet. Front. Physiol. 10, 1–20 (2019). source
• Not checked yetcites [52] Lin, N., Zhang, H. & Su, Q. Advanced glycation end-products induce injury to pancreatic beta cells through oxidative stress. Diabetes Metab. 38, 250–257 (2012). source
• Not checked yetcites [53] Song, B. J. et al. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol. 3, 109–123 (2014). source

In the paper

“In addition to an AGE, a RAGE binds diverse ligands, such as members of the S100 protein family, amyloid-β peptides (Aβ), prions, and high-mobility group protein B1 (HMGB1), which alter cellular functions and contribute to various pathophysiologies42–44.”

What the sources say

• Not checked yetcites [42] Dhumale, S. S., Waghela, B. N. & Pathak, C. Quercetin protects necrotic insult and promotes apoptosis by attenuating the expression of RAGE and its ligand HMGB1 in human breast adenocarcinoma cells. IUBMB Life 67, 361–373 (2015). source
• Not checked yetcites [43] Donato, R. RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr. Mol. Med. 7, 711–724 (2007). source
• Not checked yetcites [44] Jeong, J. et al. Soluble RAGE attenuates AngII-induced endothelial hyperpermeability by disrupting HMGB1-mediated crosstalk between AT1R and RAGE. Exp. Mol. Med. 51, 1–15 (2019). source

In the paper

“Chronic hyperglycemia, frequently observed in experimental models and human diabetes, exhibits elevated AGE formation, serum AGE levels, RAGE expression, and AGE-RAGE interactions. Consequently, these changes lead to increased oxidative stress, insulin resistance, inflammation, pancreatic β-cell dysfunction with apoptosis, and eventually diabetic complications, including retinopathy, neuropathy, c”

What the sources say

• Not checked yetcites [47] Roshandel, D. et al. DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes. Clin. Epigenetics 12, 1–16 (2020). source
• Not checked yetcites [48] Le Bagge, S., Fotheringham, A. K., Leung, S. S. & Forbes, J. M. Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes. Med. Res. Rev. 1–20, https://doi.org/10.1002/med.21654 (2020). source
• Not checked yetcites [49] Egana-Gorrono, L. et al. Receptor for advanced glycation end products (RAGE) and mechanisms and therapeutic opportunities in diabetes and cardiovascular disease: insights from human subjects and animal models. Front. Cardiovasc. Med. 7, 1–15 (2020). source
• Not checked yetcites [50] Yang, P., Feng, J., Peng, Q., Liu, X. & Fan, Z. Advanced glycation end products: potential mechanism and therapeutic target in cardiovascular complications under diabetes. Oxid. Med. Cell. Longev. 2019, 1–12 (2019).

In the paper

“Activation of these proteins usually increases oxidative stress and inflammation that, in turn, promotes RAGE expression in a positive feed-forward loop, contributing to chronic disease development39–41.”

What the sources say

• Not checked yetcites [39] Senatus, L. M. & Schmidt, A. M. The AGE-RAGE axis: implications for age-associated arterial diseases. Front. Genet. 8, 1–10 (2017). source
• Not checked yetcites [40] Xue, J. et al. The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs. Biochemistry 53, 3327–3335 (2014). source
• Not checked yetcites [41] Bongarzone, S., Savickas, V., Luzi, F. & Gee, A. D. Targeting the receptor for advanced glycation endproducts (RAGE): a medicinal chemistry perspective. J. Medicinal Chem. 60, 7213–7232 (2017). source

In the paper

“In humans, serum contains AGE peptides and free AGE adducts. AGE peptides are generally filtered by renal glomeruli and further reabsorbed by proximal convoluted tubules and eliminated from the body in the form of free AGE adducts in the urine66,67.”

What the sources say

• Not checked yetcites [66] Rabbani, N. & Thornalley, P. J. Advanced glycation end products in the pathogenesis of chronic kidney disease. Kidney Int. 93, 803–813 (2018). source
• Not checked yetcites [67] Bettiga, A. et al. The Modern Western Diet Rich in Advanced Glycation End-Products (AGEs): an overview of its impact on obesity and early progression of renal pathology. Nutrients 11, E1748 (2019). source

In the paper

“The accumulation and exposure to AGEs exacerbate oxidative stress and inflammation and initiate the oxidation of low-density lipoproteins (LDLs), which are harmful to cardiovascular function.”

What the sources say

• Not checked yetcites [55] Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011). source
• Not checked yetcites [56] Xu, J. et al. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell. Physiol. Biochem. 48, 705–717 (2018). source
• Not checked yetcites [57] Lim, M. et al. Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. Ann. N. Y. Acad. Sci. 1150, 311–315 (2008). source
• Not checked yetcites [59] Goldin, A., Beckman, J. A., Schmidt, A. M. & Creager, M. A. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114, 597–605 (2006). source

In the paper

“Restriction of dietary AGEs can reduce and/or reverse these effects by enhancing insulin sensitivity and upregulating AGE-R1 and SIRT1 expression while suppressing NF-κB, tumor necrosis factor-alpha (TNF-α), leptin, and serum AGEs in type 2 DM55.”

What the sources say

• Not checked yetcites [55] Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011). source

In the paper

“In addition, the AGE-RAGE interaction further instigates pericyte apoptosis, vascular inflammation and permeability, and blood-tissue barrier breakdown56.”

What the sources say

• Not checked yetcites [56] Xu, J. et al. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell. Physiol. Biochem. 48, 705–717 (2018). source

In the paper

“In addition, AGEs can be produced in renal mesangial cells and induce the expression of monocyte chemoattractant protein-1 (MCP-1).”

What the sources say

• Not checked yetcites [70] Frimat, M. et al. Kidney, heart and brain: three organs targeted by ageing and glycation. Clin. Sci. 131, 1069–1092 (2017). source
• Not checked yetcites [71] Kumar Pasupulati, A., Chitra, P. S. & Reddy, G. B. Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy. Biomol. Concepts 7, 293–309 (2016). source

In the paper

“Increased circulating AGEs can accumulate in the renal glomeruli and enhance collagen and laminin production in the extracellular matrix together with proximal tubular senescence, oxidative stress, and inflammatory processes66.”

What the sources say

• Not checked yetcites [66] Rabbani, N. & Thornalley, P. J. Advanced glycation end products in the pathogenesis of chronic kidney disease. Kidney Int. 93, 803–813 (2018). source

In the paper

“Adipose tissues also produce molecular RAGE ligands (such as HMGB-1) and RAGE-inducible molecules (e.g., MCP-1 and IL-6). Upon RAGE interaction, these bound molecules activate their own production in adipose tissues, suggesting a causal role of RAGE signaling in the inflammatory pathway49,67.”

What the sources say

• Not checked yetcites [49] Egana-Gorrono, L. et al. Receptor for advanced glycation end products (RAGE) and mechanisms and therapeutic opportunities in diabetes and cardiovascular disease: insights from human subjects and animal models. Front. Cardiovasc. Med. 7, 1–15 (2020). source
• Not checked yetcites [67] Bettiga, A. et al. The Modern Western Diet Rich in Advanced Glycation End-Products (AGEs): an overview of its impact on obesity and early progression of renal pathology. Nutrients 11, E1748 (2019). source

In the paper

“In addition to dietary AGEs, endogenous AGEs can be trapped and accumulated in adipose tissues, and AGE accumulation can be prevented by RAGE inhibition77.”

What the sources say

• Not checked yetcites [77] Gaens, K. H. et al. Nepsilon-(carboxymethyl)lysine-receptor for advanced glycation end product axis is a key modulator of obesity-induced dysregulation of adipokine expression and insulin resistance. Arteriosclerosis, Thrombosis, Vasc. Biol. 34, 1199–1208 (2014). source

In the paper

“Aggregated AGEs can activate the JNK, Iκ-B kinase (IKK), NF-κB, and TNF-α pathways to trigger hypothalamic insulin and leptin resistance, resulting in hypothalamic dysfunction, imbalanced energy control, and subsequently elevated food consumption and body weight with obesity and metabolic syndromes78.”

What the sources say

• Not checked yetcites [78] Sergi, D., Boulestin, H., Campbell, F. M. & Williams, L. M. The role of dietary advanced glycation end products in metabolic dysfunction. Mol. Nutr. Food Res. e1900934, https://doi.org/10.1002/mnfr.201900934 (2020). source

In the paper

“The interaction of AGE-RAGE augments the production of proinflammatory cytokines and suppresses osteoblast differentiation via the Wnt, PI3K, and ERK1/2 signaling pathways83.”

What the sources say

• Not checked yetcites [83] Li, G., Xu, J. & Li, Z. Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling. Biochem. Biophys. Res. Commun. 423, 684–689 (2012). source

In the paper

“The binding of AGEs to RAGE triggers extracellular matrix glycation, NADPH oxidase activity, local hypoxia, VEGF expression, and NF-κB activation to produce oxidative stress and inflammation, supporting the cancer microenvironment and promoting tumoral angiogenesis and proliferation32,87.”

What the sources say

• Not checked yetcites [32] Rojas, A., Anazco, C., Gonzalez, I. & Araya, P. Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer. Carcinogenesis 39, 515–521 (2018). source
• Not checked yetcites [87] Foster, D. et al. AGE metabolites: a biomarker linked to cancer disparity? Cancer Epidemiol. Biomark. Prev. 23, 2186–2191 (2014). source

In the paper

“In bone, accumulated AGEs can increase osteoclast generation while decreasing osteoblast growth and differentiation.”

What the sources say

• Not checked yetcites [80] Okazaki, K. et al. Advanced glycation end products (AGEs), but not high glucose, inhibit the osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix expression, and inhibit cell growth and increasing cell apoptosis. Calcif. Tissue Int. 91, 286–296 (2012). source
• Not checked yetcites [81] Liu, J. et al. AGEs induce apoptosis in rat osteoblast cells by activating the caspase-3 signaling pathway under a high-glucose environment in vitro. Appl. Biochem. Biotechnol. 178, 1015–1027 (2016). source
• Not checked yetcites [82] Zhu, S. Y. et al. Advanced oxidation protein products induce pre-osteoblast apoptosis through a nicotinamide adenine dinucleotide phosphate oxidase-dependent, mitogen-activated protein kinases-mediated intrinsic apoptosis pathway. Aging Cell 17, 1–15 (2018). source

In the paper

“The intestinal microbiota produces deglycating enzymes to digest AGEs, which are utilized for energy production.”

What the sources say

• Not checked yetcites [98] Qu, W. et al. Dietary advanced glycation end products modify gut microbial composition and partially increase colon permeability in rats. Mol. Nutr. Food Res. 61, 1–14 (2017). source

In the paper

“In the body, less than 30% of dietary AGEs are absorbed in the intestine after ingestion, and less than 15% are excreted in urine and feces, leading to a hypothesis that the remaining unabsorbed AGEs are degraded by gut microorganisms97.”

What the sources say

• Not checked yetcites [97] Tuohy, K. M. et al. Metabolism of Maillard reaction products by the human gut microbiota–implications for health. Mol. Nutr. Food Res. 50, 847–857 (2006). source

In the paper

“Elevated accumulation of AGEs can enhance gut barrier dysfunction, intestinal permeability, and bacterial translocation by stimulating the production and release of proinflammatory cytokines, potentially toxic metabolites and bacterial products, as well as causing intestinal epithelial cell damage, contributing to systemic endotoxemia, inflammation, and multiorgan injury98.”

What the sources say

• Not checked yetcites [98] Qu, W. et al. Dietary advanced glycation end products modify gut microbial composition and partially increase colon permeability in rats. Mol. Nutr. Food Res. 61, 1–14 (2017). source

In the paper

“The gut microbiota plays a critical role in regulating body function by producing diverse metabolites and influencing the gut-liver-brain axis and other pathways, such as immune system pathways.”

What the sources say

• Not checked yetcites [95] Gentile, C. L. & Weir, T. L. The gut microbiota at the intersection of diet and human health. Science 362, 776–780 (2018). source
• Not checked yetcites [96] Dinan, T. G. & Cryan, J. F. Gut-brain axis in 2016: brain-gut-microbiota axis - mood, metabolism and behaviour. Nat. Rev. Gastroenterol. Hepatol. 14, 69–70 (2017). source

In the paper

“Oxidative stress can also be generated due to AGE formation in the brain. This feed-forward process creates a vicious cycle that exacerbates oxidative damage with the subsequent initiation and progression of neurodegenerative diseases4,103.”

What the sources say

• Not checked yetcites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source
• Not checked yetcites [103] Srikanth, V. et al. Advanced glycation endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol. Aging 32, 763–777 (2011). source

In the paper

“After binding with S100, RAGE also contributes to the epithelial-mesenchymal cell transition and cell migration, which is associated with tumor invasion and metastasis in cervical cancer and osteosarcomas, suggesting a contributing role for RAGE in tumor malignancy92.”

What the sources say

• Not checked yetcites [92] Kataoka, K. et al. S100A7 promotes the migration and invasion of osteosarcoma cells via the receptor for advanced glycation end products. Oncol. Lett. 3, 1149–1153 (2012). source

In the paper

“In addition to AGEs and AGE adducts, HMGB1 and Aβ can bind RAGEs to activate the NF-κB, ERK1/2, p38, JNK, PI3K, Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways, leading to neuronal cell death and neurodegeneration112.”

What the sources say

• Not checked yetcites [112] Bortolotto, V. & Grilli, M. Every cloud has a silver lining: proneurogenic effects of abeta oligomers and HMGB-1 via activation of the RAGE-NF-kappaB axis. CNS Neurol. Disord. Drug Targets 16, 1066–1079 (2017). source

In the paper

“Additionally, the accumulation of AGEs and the AGE-RAGE interaction greatly induce reactive gliosis and the NF-κB proinflammatory pathway, leading to cellular stress, activated gliosis, and eventually neuronal degeneration105.”

What the sources say

• Not checked yetcites [105] Wang, C.-Y. et al. Trientine reduces BACE1 activity and mitigates amyloidosis via the AGE/RAGE/NF-κB pathway in a transgenic mouse model of Alzheimer’s disease. Antioxid. Redox Signal 19, 2024–2039 (2013). source

In the paper

“Activated microglial cells produce and secrete AGE-albumin to induce RAGE expression in neurons and promote neuronal cell death, thereby contributing to neurodegenerative disorders4,108.”

What the sources say

• Not checked yetcites [4] Byun, K. et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol. Therapeutics 177, 44–55 (2017). source
• Not checked yetcites [108] Byun, K. et al. Activated microglial cells synthesize and secrete AGE-albumin. Anat. Cell Biol. 45, 47–52 (2012). source

In the paper

“One of the most abundant AGE-protein adducts in the brain is the AGE-albumin adduct, which was confirmed by mass spectral analysis, and causes RAGE overexpression in primary neurons in human AD brains.”

What the sources say

• Not checked yetcites [111] Byun, K. et al. Induction of neuronal death by microglial AGE-albumin: implications for Alzheimer’s disease. PloS One 7, 1–11 (2012). source

In the paper

“AGEs also suppress SIRT1 expression and stimulate inducible nitric oxide synthase (iNOS) and caspase-3 to enhance neuronal apoptosis and/or degeneration with elevated gliosis110.”

What the sources say

• Not checked yetcites [110] Wong, A. et al. Advanced glycation endproducts co-localize with inducible nitric oxide synthase in Alzheimer’s disease. Brain Res. 920, 32–40 (2001). source

In the paper

“Aβ is also produced by the AGE-albumin-RAGE interaction, which in turn supports AGE-albumin adduct formation in a positive feed-forward cycle.”

What the sources say

• Not checked yetcites [111] Byun, K. et al. Induction of neuronal death by microglial AGE-albumin: implications for Alzheimer’s disease. PloS One 7, 1–11 (2012). source

In the paper

“Accumulated AGEs can accelerate the formation of Aβ, tau, and amyloid precursor protein (APP) and induce the hyperphosphorylation of tau and the cross-linking of AGE-Aβ, leading to an increase in these aggregates109.”

What the sources say

• Not checked yetcites [109] Chen, K., Maley, J. & Yu, P. H. Potential inplications of endogenous aldehydes in beta-amyloid misfolding, oligomerization and fibrillogenesis. J. Neurochem. 99, 1413–1424 (2006). source

In the paper

“Endogenous and exogenous AGEs provoke the initiation and progression of NAFLD.”

• Also stated in: § AGEs and liver diseases · plain

  “However, consumption of dietary AGEs from sources such as fructose- or sucrose-enriched diets and/or soft drinks can worsen liver fibrosis faster than consumption of endogenous AGEs.”

What the sources say

• Not checked yetcites [55] Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011). source
• Not checked yetcites [56] Xu, J. et al. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell. Physiol. Biochem. 48, 705–717 (2018). source
• Not checked yetcites [57] Lim, M. et al. Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. Ann. N. Y. Acad. Sci. 1150, 311–315 (2008). source
• Not checked yetcites [124] Leung, C. et al. Dietary glycotoxins exacerbate progression of experimental fatty liver disease. J. Hepatol. 60, 832–838 (2014). source
• Not checked yetcites [125] Rolo, A. P., Teodoro, J. S. & Palmeira, C. M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59–69 (2012). source
• Not checked yetcites [126] Jiang, J. X. et al. Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-alpha-converting enzyme activity in mice. Hepatology 58, 1339–1348 (2013). source

In the paper

“AGEs cross-linked with α-synuclein are also present in PD brains, resulting in the aggregation of α-synuclein toxic oligomers115,116.”

What the sources say

• Not checked yetcites [115] Guerrero, E., Vasudevaraju, P., Hegde, M. L., Britton, G. B. & Rao, K. S. Recent advances in alpha-synuclein functions, advanced glycation, and toxicity: implications for Parkinson’s disease. Mol. Neurobiol. 47, 525–536 (2013). source
• Not checked yetcites [116] Munch, G. et al. Crosslinking of alpha-synuclein by advanced glycation endproducts–an early pathophysiological step in Lewy body formation? J. Chem. Neuroanat. 20, 253–257 (2000). source

In the paper

“It is involved in the catabolism and elimination of circulating AGEs using liver sinusoidal endothelial cells and Kupffer cells.”

• Also stated in: § AGEs and liver diseases · plain

  “This function of the liver declines during the aging process and in various liver diseases, resulting in the accumulation of AGEs or their aggregates120,121.”

What the sources say

• Not checked yetcites [120] Sebekova, K., Kupcova, V., Schinzel, R. & Heidland, A. Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis - amelioration by liver transplantation. J. Hepatol. 36, 66–71 (2002). source
• Not checked yetcites [121] Fernando, D. H., Forbes, J. M., Angus, P. W. & Herath, C. B. Development and progression of non-alcoholic fatty liver disease: the role of advanced glycation end products. Int. J. Mol. Sci. 20, 1–19 (2019). source

In the paper

“The aggregation of AGEs decreases the levels of the most important cellular antioxidant peptides, glutathione (GSH), SIRT1, and tissue inhibitor of metalloproteinase 3 (TIMP3), accompanied by increased oxidative stress and inflammation, promoting inflammatory liver injury and fibrosis in experimental animal models and NAFLD patients55–57,124–126.”

What the sources say

• Not checked yetcites [55] Uribarri, J. et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011). source
• Not checked yetcites [56] Xu, J. et al. Involvement of advanced glycation end products in the pathogenesis of diabetic retinopathy. Cell. Physiol. Biochem. 48, 705–717 (2018). source
• Not checked yetcites [57] Lim, M. et al. Induction of apoptosis of Beta cells of the pancreas by advanced glycation end-products, important mediators of chronic complications of diabetes mellitus. Ann. N. Y. Acad. Sci. 1150, 311–315 (2008). source
• Not checked yetcites [124] Leung, C. et al. Dietary glycotoxins exacerbate progression of experimental fatty liver disease. J. Hepatol. 60, 832–838 (2014). source
• Not checked yetcites [125] Rolo, A. P., Teodoro, J. S. & Palmeira, C. M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 52, 59–69 (2012). source
• Not checked yetcites [126] Jiang, J. X. et al. Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-alpha-converting enzyme activity in mice. Hepatology 58, 1339–1348 (2013). source

In the paper

“AGE-albumin, the most abundant AGE product in the human PD brain, is synthesized by activated microglial cells.”

What the sources say

• Not checked yetcites [119] Bayarsaikhan, E. et al. Microglial AGE-albumin is critical for neuronal death in Parkinson’s disease: a possible implication for theranostics. Int. J. Nanomed. 10(Spec Iss), 281–292 (2015).

In the paper

“Moreover, RAGE can interact with S100 in PD brains, activating the NF-κB and TNF-α signaling pathways to promote dopaminergic neuronal death and subsequent neurodegeneration in PD117,118.”

What the sources say

• Not checked yetcites [117] Sathe, K. et al. S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain J. Neurol. 135, 3336–3347 (2012). source
• Not checked yetcites [118] Abdelsalam, R. M. & Safar, M. M. Neuroprotective effects of vildagliptin in rat rotenone Parkinson’s disease model: role of RAGE-NFkappaB and Nrf2-antioxidant signaling pathways. J. Neurochem. 133, 700–707 (2015). source

In the paper

“Ethanol metabolism primarily occurs in the liver in three major steps: (1) ethanol oxidation to acetaldehyde, (2) acetaldehyde metabolism to acetate, and (3) acetate catabolism to H2O and CO2132–134.”

What the sources say

• Not checked yetcites [132] Purohit, V., Gao, B. & Song, B. J. Molecular mechanisms of alcoholic fatty liver. Alcohol. Clin. Exp. Res. 33, 191–205 (2009). source
• Not checked yetcites [133] Thiele, G. M., Klassen, L. W. & Tuma, D. J. Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol. Biol. 447, 235–257 (2008). source
• Not checked yetcites [134] Zakhari, S. Overview: how is alcohol metabolized by the body? Alcohol Res. Health. 29, 245–254 (2006).

In the paper

“Increased amounts of RAGE are also observed in the liver of hepatocellular carcinoma (HCC), and its level is significantly greater than it is liver affected by hepatitis and healthy liver specimens.”

• Also stated in: § AGEs and liver diseases · plain

  “The amounts of serum AGEs are also higher in HCC than in NASH and healthy liver specimens.”

What the sources say

• Not checked yetcites [129] Hiwatashi, K. et al. A novel function of the receptor for advanced glycation end-products (RAGE) in association with tumorigenesis and tumor differentiation of HCC. Ann. Surg. Oncol. 15, 923–933 (2008). source
• Not checked yetcites [130] Takino, J., Yamagishi, S. & Takeuchi, M. Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression. World J. Gastroenterol. 18, 1781–1788 (2012). source
• Not checked yetcites [131] Yang, Y. et al. Pioglitazone, a PPARgamma agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling. Mol. Carcinog. 54, 1584–1595 (2015). source

In the paper

“In HCC, the AGE-RAGE interaction is associated with angiogenesis and tumor proliferation and invasion, which are ameliorated by RAGE inhibition.”

What the sources say

• Not checked yetcites [129] Hiwatashi, K. et al. A novel function of the receptor for advanced glycation end-products (RAGE) in association with tumorigenesis and tumor differentiation of HCC. Ann. Surg. Oncol. 15, 923–933 (2008). source
• Not checked yetcites [130] Takino, J., Yamagishi, S. & Takeuchi, M. Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression. World J. Gastroenterol. 18, 1781–1788 (2012). source
• Not checked yetcites [131] Yang, Y. et al. Pioglitazone, a PPARgamma agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling. Mol. Carcinog. 54, 1584–1595 (2015). source

In the paper

“Accumulated AGEs and AGE-RAGE interactions in these cells augment the generation of ROS and the activation of MAPK and NF-κB pathways, leading to inflammatory cell death in the parenchyma and tissue remodeling processes during fibrosis127,128.”

What the sources say

• Not checked yetcites [127] Fehrenbach, H., Weiskirchen, R., Kasper, M. & Gressner, A. M. Up-regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to myofibroblasts. Hepatology 34, 943–952 (2001). source
• Not checked yetcites [128] Leung, C. et al. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease. World J. Gastroenterol. 22, 8026–8040 (2016). source

In the paper

“Upon consumption, ethanol is absorbed via simple diffusion in the small intestine into the blood and rapidly circulates throughout the body6.”

What the sources say

• Not checked yetcites [6] Jamal, M. et al. in Neuroscience of Alcohol (ed Victor R. Preedy) 39–46 (Academic Press, 2019).

In the paper

“However, treatment with an antioxidant can halt AA-AGE adduct formation, supporting the idea that AA-AGE adducts can be generated from a Schiff base product similar to AA adducts and AGEs.”

What the sources say

• Not checked yetcites [168] Freeman, T. L. et al. Recent advances in alcohol-induced adduct formation. Alcohol. Clin. Exp. Res. 29, 1310–1316 (2005). source

In the paper

“Cytosolic ADH is a major enzyme that catalyzes the oxidative metabolism of ethanol to acetaldehyde by using the cofactor nicotinamide adenine dinucleotide (NAD+) converted to NADH132–134.”

What the sources say

• Not checked yetcites [132] Purohit, V., Gao, B. & Song, B. J. Molecular mechanisms of alcoholic fatty liver. Alcohol. Clin. Exp. Res. 33, 191–205 (2009). source
• Not checked yetcites [133] Thiele, G. M., Klassen, L. W. & Tuma, D. J. Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol. Biol. 447, 235–257 (2008). source
• Not checked yetcites [134] Zakhari, S. Overview: how is alcohol metabolized by the body? Alcohol Res. Health. 29, 245–254 (2006).

In the paper

“After chronic and/or large amounts of ethanol intake, CYP2E1, the major component of the microsomal ethanol oxidizing system (MEOS) with a higher km (~10 mM for ethanol) than that of ADH (km <1 mM for ethanol), is also involved in ethanol metabolism through an NADPH-dependent pathway.”

• Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain

  “In contrast to those of ADH and catalase, CYP2E1 expression and activity are usually induced by ethanol and other substances, such as dietary fats.”

• Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain

  “The induction and activation of CYP2E1, in turn, contribute to alcohol- and nonalcohol-induced pathophysiology136–144.”

What the sources say

• Not checked yetcites [136] Yun, J.-W. et al. Binge alcohol promotes hypoxic liver injury through a CYP2E1–HIF-1α-dependent apoptosis pathway in mice and humans. Free Radic. Biol. Med. 77, 183–194 (2014). source
• Not checked yetcites [137] Jeong, K.-S. et al. Cytochrome P450 2E1 (CYP2E1)-dependent production of a 37-kDa acetaldehyde–protein adduct in the rat liver. Arch. Biochem. Biophys. 384, 81–87 (2000). source
• Not checked yetcites [138] Cederbaum, A. I., Lu, Y. & Wu, D. Role of oxidative stress in alcohol-induced liver injury. Arch. Toxicol. 83, 519–548 (2009). source
• Not checked yetcites [139] Abdelmegeed, M. A. et al. Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J. Hepatol. 57, 860–866 (2012). source
• Not checked yetcites [140] Knockaert, L., Descatoire, V., Vadrot, N., Fromenty, B. & Robin, M. A. Mitochondrial CYP2E1 is sufficient to mediate oxidative stress and cytotoxicity induced by ethanol and acetaminophen. Toxicol. Vitro 25, 475–484 (2011). source
• Not checked yetcites [141] Leung, T. M. & Nieto, N. CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. J. Hepatol. 58, 395–398 (2013). source
• Not checked yetcites [142] Song, B. J., Akbar, M., Jo, I., Hardwick, J. P. & Abdelmegeed, M. A. Translational implications of the alcohol-metabolizing enzymes, including cytochrome P450-2E1, in alcoholic and nonalcoholic liver disease. Adv. Pharmacol. 74, 303–372 (2015). source
• Not checked yetcites [143] Seitz, H. K. The role of cytochrome P4502E1 in the pathogenesis of alcoholic liver disease and carcinogenesis. Chem. Biol. Interact. 316, 108918 (2020). source
• Not checked yetcites [144] Song, B. J. et al. Contributing roles of CYP2E1 and other cytochrome P450 isoforms in alcohol-related tissue injury and carcinogenesis. Adv. Exp. Med. Biol. 1164, 73–87 (2019). source

In the paper

“The formation of AA-AGE adducts can be observed after chronic alcohol exposure.”

• Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain

  “These AA-AGE adducts exhibit similar properties (e.g., brown color and polymerization) as the AGE adducts cross-link with sugar molecules, and they are different from MAA adducts formed by AA and MDA interactions.”

What the sources say

• Not checked yetcites [168] Freeman, T. L. et al. Recent advances in alcohol-induced adduct formation. Alcohol. Clin. Exp. Res. 29, 1310–1316 (2005). source

In the paper

“Catalase present in peroxisomes may participate in ethanol oxidation in the presence of H2O2132–134, although this enzyme appears to play no major role in hepatic ethanol metabolism under physiological conditions due to the limited supply of H2O2135.”

What the sources say

• Not checked yetcites [132] Purohit, V., Gao, B. & Song, B. J. Molecular mechanisms of alcoholic fatty liver. Alcohol. Clin. Exp. Res. 33, 191–205 (2009). source
• Not checked yetcites [133] Thiele, G. M., Klassen, L. W. & Tuma, D. J. Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol. Biol. 447, 235–257 (2008). source
• Not checked yetcites [134] Zakhari, S. Overview: how is alcohol metabolized by the body? Alcohol Res. Health. 29, 245–254 (2006).
• Not checked yetcites [135] Lieber, C. S. Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998)–a review. Alcohol. Clin. Exp. Res. 23, 991–1007 (1999).

In the paper

“In the second step, acetaldehyde is converted to acetate due to the low km (for acetaldehyde) mitochondrial aldehyde dehydrogenase 2 isozyme (ALDH2) in humans145.”

• Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain

  “Notably, CYP2E1 also takes part in this step with NADPH acting as a cofactor to convert acetaldehyde to acetate146.”

What the sources say

• Not checked yetcites [145] Klyosov, A. A., Rashkovetsky, L. G., Tahir, M. K. & Keung, W. M. Possible role of liver cytosolic and mitochondrial aldehyde dehydrogenases in acetaldehyde metabolism. Biochemistry 35, 4445–4456 (1996). source
• Not checked yetcites [146] Kunitoh, S. et al. Acetaldehyde as well as ethanol is metabolized by human CYP2E1. J. Pharmacol. Exp. Therapeutics 280, 527–532 (1997).

In the paper

“In contrast, CYP2E1 is widely expressed throughout the brain, such as in the cerebral cortex, hippocampus, and cerebellum.”

• Also stated in: § Alcohol metabolism (see summary in Fig. 1) · hedged

  “Similar to that in the liver, brain CYP2E1 is also inducible by ethanol and may therefore play a key role in cerebral ethanol metabolism, especially after chronic and/or binge alcohol intake151–155.”

What the sources say

• Not checked yetcites [151] Hansson, T., Tindberg, N., Ingelman-Sundberg, M. & Kohler, C. Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system. Neuroscience 34, 451–463 (1990). source
• Not checked yetcites [152] Yadav, S., Dhawan, A., Singh, R. L., Seth, P. K. & Parmar, D. Expression of constitutive and inducible cytochrome P450 2E1 in rat brain. Mol. Cell. Biochem. 286, 171–180 (2006). source
• Not checked yetcites [153] Upadhya, S. C., Tirumalai, P. S., Boyd, M. R., Mori, T. & Ravindranath, V. Cytochrome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization. Arch. Biochem Biophys. 373, 23–34 (2000). source
• Not checked yetcites [154] Anandatheerthavarada, H. K. et al. Induction of brain cytochrome P-450IIE1 by chronic ethanol treatment. Brain Res. 601, 279–285 (1993). source
• Not checked yetcites [155] Montoliu, C., Valles, S., Renau-Piqueras, J. & Guerri, C. Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J. Neurochem. 63, 1855–1862 (1994). source

In the paper

“Finally, the acetate that is produced is further degraded to CO2 and H2O, ending the final step of ethanol oxidation in the liver132–134.”

What the sources say

• Not checked yetcites [132] Purohit, V., Gao, B. & Song, B. J. Molecular mechanisms of alcoholic fatty liver. Alcohol. Clin. Exp. Res. 33, 191–205 (2009). source
• Not checked yetcites [133] Thiele, G. M., Klassen, L. W. & Tuma, D. J. Formation and immunological properties of aldehyde-derived protein adducts following alcohol consumption. Methods Mol. Biol. 447, 235–257 (2008). source
• Not checked yetcites [134] Zakhari, S. Overview: how is alcohol metabolized by the body? Alcohol Res. Health. 29, 245–254 (2006).

In the paper

“The role of CYP2E1 in brain ethanol metabolism and its association with alcohol-mediated oxidative neuronal injury155–160 and aging-related AD and PD161 have also been suggested.”

What the sources say

• Not checked yetcites [155] Montoliu, C., Valles, S., Renau-Piqueras, J. & Guerri, C. Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J. Neurochem. 63, 1855–1862 (1994). source
• Not checked yetcites [156] Montoliu, C. et al. Ethanol increases cytochrome P4502E1 and induces oxidative stress in astrocytes. J. Neurochem. 65, 2561–2570 (1995). source
• Not checked yetcites [157] Brzezinski, M. R., Boutelet-Bochan, H., Person, R. E., Fantel, A. G. & Juchau, M. R. Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain. J. Pharmacol. Exp. Therapeutics 289, 1648–1653 (1999).
• Not checked yetcites [158] Haorah, J., Knipe, B., Leibhart, J., Ghorpade, A. & Persidsky, Y. Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction. J. Leukoc. Biol. 78, 1223–1232 (2005). source
• Not checked yetcites [159] Zhong, Y. et al. Induction of brain CYP2E1 by chronic ethanol treatment and related oxidative stress in hippocampus, cerebellum, and brainstem. Toxicology 302, 275–284 (2012). source
• Not checked yetcites [160] Valencia-Olvera, A. C., Moran, J., Camacho-Carranza, R., Prospero-Garcia, O. & Espinosa-Aguirre, J. J. CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons. Toxicol. Vitro 28, 1206–1214 (2014). source
• Not checked yetcites [161] Peng, B. et al. Role of alcohol drinking in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Int. J. Mol. Sci. 21, https://doi.org/10.3390/ijms21072316 (2020). source

In the paper

“Cerebral ADH plays very little or virtually no role in ethanol metabolism in the brain compared to its action by its hepatic isoform.”

• Also stated in: § Alcohol metabolism (see summary in Fig. 1) · plain

  “However, cerebral catalase acts as the main oxidizing enzyme, accounting for more than 60% of ethanol oxidation in the brain under normal conditions147.”

What the sources say

• Not checked yetcites [147] Zimatkin, S. M., Pronko, S. P., Vasiliou, V., Gonzalez, F. J. & Deitrich, R. A. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol. Clin. Exp. Res. 30, 1500–1505 (2006). source

In the paper

“Furthermore, the remaining unmetabolized ethanol, acetaldehyde, and acetate can be distributed to many other organs, including the heart, lung, kidney, pancreas, and brain, causing damage in various peripheral tissues and neurobehavioral effects caused by damage to the brain.”

In the paper

“Similar to the liver, ethanol oxidizing enzymes are also functional in the brain and include ADH, catalase, CYP2E1, and ALDH2, which make different contributions.”

What the sources say

• Not checked yetcites [147] Zimatkin, S. M., Pronko, S. P., Vasiliou, V., Gonzalez, F. J. & Deitrich, R. A. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol. Clin. Exp. Res. 30, 1500–1505 (2006). source

In the paper

“MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.”

What the sources say

• Not checked yetcites [172] Doorn, J. A., Hurley, T. D. & Petersen, D. R. Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem. Res. Toxicol. 19, 102–110 (2006). source
• Not checked yetcites [173] Galligan, J. J. et al. Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: functional independence of ATPase activity and chaperone function. Free Radic. Biol. Med. 73, 411–420 (2014). source
• Not checked yetcites [174] Sampey, B. P., Stewart, B. J. & Petersen, D. R. Ethanol-induced modulation of hepatocellular extracellular signal-regulated kinase-1/2 activity via 4-hydroxynonenal. J. Biol. Chem. 282, 1925–1937 (2007). source
• Not checked yetcites [175] Shearn, C. T. et al. Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis. Free Radic. Biol. Med. 65, 680–692 (2013). source
• Not checked yetcites [176] Shearn, C. T., Backos, D. S., Orlicky, D. J., Smathers-McCullough, R. L. & Petersen, D. R. Identification of 5’ AMP-activated kinase as a target of reactive aldehydes during chronic ingestion of high concentrations of ethanol. J. Biol. Chem. 289, 15449–15462 (2014). source
• Not checked yetcites [177] Hartley, D. P. & Petersen, D. R. Co-metabolism of ethanol, ethanol-derived acetaldehyde, and 4-hydroxynonenal in isolated rat hepatocytes. Alcohol. Clin. Exp. Res. 21, 298–304 (1997). source

In the paper

“Finally, mitochondrial ALDH2 is the final enzyme for converting acetaldehyde to acetate148, although acetaldehyde is locally produced in the brain due to its very limited ability to cross the BBB162.”

What the sources say

• Not checked yetcites [148] Deng, X.-s & Deitrich, R. A. Putative role of brain acetaldehyde in ethanol addiction. Curr. Drug Abus. Rev. 1, 3–8 (2008). source
• Not checked yetcites [162] Zimatkin, S. M. Histochemical study of aldehyde dehydrogenase in the rat CNS. J. Neurochem. 56, 1–11 (1991). source

In the paper

“The formation of adduct proteins can prolong protein half-lives and accumulate as aggregated proteins.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged

  “Therefore, when lysine residues are already occupied by reactive acetaldehyde, lipid aldehydes, AGEs, or AA, adducts persist for extended periods of time and may end up as aggregated proteins due to the lack of free lysine needed for ubiquitin conjugation and subsequent proteolysis.”

What the sources say

• Not checked yetcites [182] Song, B. J. Ethanol-inducible cytochrome P450 (CYP2E1): biochemistry, molecular biology and clinical relevance: 1996 update. Alcohol. Clin. Exp. Res. 20, 138a–146a (1996). source
• Not checked yetcites [183] Song, B. J., Veech, R. L., Park, S. S., Gelboin, H. V. & Gonzalez, F. J. Induction of rat hepatic N-nitrosodimethylamine demethylase by acetone is due to protein stabilization. J. Biol. Chem. 264, 3568–3572 (1989). source
• Not checked yetcites [184] Roberts, B. J., Shoaf, S. E., Jeong, K. S. & Song, B. J. Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration and withdrawal: Evidence that CYP2E1 possesses a rapid phase half-life of 6 hours or less. Biochem. Biophys. Res. Commun. 205, 1064–1071 (1994). source
• Not checked yetcites [185] Abdelmegeed, M. A., Moon, K.-H., Chen, C., Gonzalez, F. J. & Song, B.-J. Role of cytochrome P450 2E1 in protein nitration and ubiquitin-mediated degradation during acetaminophen toxicity. Biochem. Pharmacol. 79, 57–66 (2010). source
• Not checked yetcites [186] Roberts, B. J., Song, B. J., Soh, Y., Park, S. S. & Shoaf, S. E. Ethanol induces CYP2E1 by protein stabilization. Role of ubiquitin conjugation in the rapid degradation of CYP2E1. J. Biol. Chem. 270, 29632–29635 (1995). source

In the paper

“For instance, ethanol intake can induce 4-HNE to interact with cytochrome C oxidase (complex IV) and ALDH2 in the mitochondria, GRP78 and disulfide isomerase in the ER, and ERK1/2, phosphatase and tensin homolog (PTEN), AMP-activated protein kinase (AMPK), and gamma-glutamylcysteine synthetase (GCS) in the cytosol.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain

  “These adduct formations inactivate their target proteins and result in the accumulation of lipid aldehydes, ER stress, mitochondrial dysfunction, cell signaling alteration, and potentially multitissue injury172–177.”

What the sources say

• Not checked yetcites [172] Doorn, J. A., Hurley, T. D. & Petersen, D. R. Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem. Res. Toxicol. 19, 102–110 (2006). source
• Not checked yetcites [173] Galligan, J. J. et al. Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: functional independence of ATPase activity and chaperone function. Free Radic. Biol. Med. 73, 411–420 (2014). source
• Not checked yetcites [174] Sampey, B. P., Stewart, B. J. & Petersen, D. R. Ethanol-induced modulation of hepatocellular extracellular signal-regulated kinase-1/2 activity via 4-hydroxynonenal. J. Biol. Chem. 282, 1925–1937 (2007). source
• Not checked yetcites [175] Shearn, C. T. et al. Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis. Free Radic. Biol. Med. 65, 680–692 (2013). source
• Not checked yetcites [176] Shearn, C. T., Backos, D. S., Orlicky, D. J., Smathers-McCullough, R. L. & Petersen, D. R. Identification of 5’ AMP-activated kinase as a target of reactive aldehydes during chronic ingestion of high concentrations of ethanol. J. Biol. Chem. 289, 15449–15462 (2014). source
• Not checked yetcites [177] Hartley, D. P. & Petersen, D. R. Co-metabolism of ethanol, ethanol-derived acetaldehyde, and 4-hydroxynonenal in isolated rat hepatocytes. Alcohol. Clin. Exp. Res. 21, 298–304 (1997). source

In the paper

“In contrast, ALDH1B and other isoforms may be involved in acetaldehyde metabolism in rodents145,147,163.”

What the sources say

• Not checked yetcites [145] Klyosov, A. A., Rashkovetsky, L. G., Tahir, M. K. & Keung, W. M. Possible role of liver cytosolic and mitochondrial aldehyde dehydrogenases in acetaldehyde metabolism. Biochemistry 35, 4445–4456 (1996). source
• Not checked yetcites [147] Zimatkin, S. M., Pronko, S. P., Vasiliou, V., Gonzalez, F. J. & Deitrich, R. A. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol. Clin. Exp. Res. 30, 1500–1505 (2006). source
• Not checked yetcites [163] Stagos, D. et al. Aldehyde dehydrogenase 1B1: molecular cloning and characterization of a novel mitochondrial acetaldehyde-metabolizing enzyme. Drug Metab. Dispos. 38, 1679–1687 (2010). source

In the paper

“Acetaldehyde adducts (AA adducts) are formed by the interaction of acetaldehyde, a direct metabolite of ethanol oxidation and a human carcinogen, with certain amino acids, including lysine, cysteine, and aromatic amino acids.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain

  “The proteins commonly bound to acetaldehyde to produce AA adducts include membrane proteins of the red blood cells (erythrocytes), hemoglobin (oxygen transport), tubulin (cellular structure), lipoproteins (lipid transport), albumin (blood), and collagen (connective tissue)167,169,180.”

What the sources say

• Not checked yetcites [167] Tuma, D. J. & Casey, C. A. Dangerous byproducts of alcohol breakdown–focus on adducts. Alcohol Res. Health. 27, 285–290 (2003).
• Not checked yetcites [169] Worrall, S., de Jersey, J. & Wilce, P. A. Comparison of the formation of proteins modified by direct and indirect ethanol metabolites in the liver and blood of rats fed the lieber–de carli liquid diet. Alcohol Alcohol. 35, 164–170 (2000). source
• Not checked yetcites [180] Patel, V. B., Worrall, S., Emery, P. W. & Preedy, V. R. Protein adduct species in muscle and liver of rats following acute ethanol administration. Alcohol Alcohol. 40, 485–493 (2005). source

In the paper

“AA adducts are produced in two separate pathways that yield two different types of adducts, depending on the existing conditions.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain

  “In the second pathway, the initial step is the formation of a Schiff base adduct followed by several rearrangements and reactions to yield diverse AA adducts168.”

What the sources say

• Not checked yetcites [168] Freeman, T. L. et al. Recent advances in alcohol-induced adduct formation. Alcohol. Clin. Exp. Res. 29, 1310–1316 (2005). source

In the paper

“In neurons, direct exposure of AA-AGE adducts to cortical neurons triggers ROS generation, leading to oxidative stress and consequently neuronal apoptosis and degeneration in a dose-dependent manner.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged

  “These effects can be prevented by treatment with the antioxidant N-acetylcysteine (NAC) or a neutralizing anti-AA-AGE antibody, suggesting a direct role for AA-AGE adducts in generating oxidative stress-induced neurotoxicity199.”

What the sources say

• Not checked yetcites [199] Takeuchi, M. et al. Neurotoxicity of acetaldehyde-derived advanced glycation end products for cultured cortical neurons. J. Neuropathol. Exp. Neurol. 62, 486–496 (2003). source

In the paper

“In addition to cerebral AA-protein adducts, ethanol intake or exposure can induce and accelerate AGE production in the brain.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain

  “Aggregation of cross-linked AGEs further upregulates RAGE expression and activation, contributing to diverse outcomes with neurobehavioral impairment, as observed in people with AUD190.”

What the sources say

• Not checked yetcites [190] Nakamura, K. et al. Acetaldehyde adducts in the brain of alcoholics. Arch. Toxicol. 77, 591–593 (2003). source

In the paper

“Furthermore, acetaldehyde can interact with dopamine (DA) to produce AA-DA adducts, including salsolinol, a neurotoxin and potent stimulant in alcohol, which is involved in the pathogenesis of AUD and PD194,195.”

What the sources say

• Not checked yetcites [194] Smith, S. L., Jennett, R. B., Sorrell, M. F. & Tuma, D. J. Acetaldehyde substoichiometrically inhibits bovine neurotubulin polymerization. J. Clin. Investig. 84, 337–341 (1989). source
• Not checked yetcites [195] Deehan, G. A. Jr, Hauser, S. R., Wilden, J. A., Truitt, W. A. & Rodd, Z. A. Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol. Front. Behav. Neurosci. 7, 1–13 (2013). source

In the paper

“Daily alcohol exposure for ten consecutive days also instigated microglial activation to synthesize and secrete AGE-albumin adducts in the hippocampus and entorhinal cortex of the rat brain.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain

  “Accumulated AGE-albumin adducts increase the expression of RAGE and activate the MAPK (JNK and p38K)-dependent cell death pathway to promote inflammation, apoptosis, and neuronal damage, which are significantly attenuated by treatment with soluble RAGE and chemical AGE inhibitors200.”

What the sources say

• Not checked yetcites [200] Byun, K. et al. Microglial AGE-albumin is critical in promoting alcohol-induced neurodegeneration in rats and humans. PloS one 9, e104699 (2014). source

In the paper

“The presence of acetaldehyde in the brain also alters DNA integrity and neuronal viability.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged

  “The dual mechanisms of simultaneously elevated AA-DNA adducts and suppressed DNA repair systems following alcohol intake may contribute to genetic instability and DNA mutations, promoting neurological pathologies192,197,198.”

What the sources say

• Not checked yetcites [53] Song, B. J. et al. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol. 3, 109–123 (2014). source
• Not checked yetcites [192] Heymann, H. M., Gardner, A. M. & Gross, E. R. Aldehyde-induced DNA and protein adducts as biomarker tools for alcohol use disorder. Trends Mol. Med 24, 144–155 (2018). source
• Not checked yetcites [197] Lamarche, F., Gonthier, B., Signorini, N., Eysseric, H. & Barret, L. Impact of ethanol and acetaldehyde on DNA and cell viability of cultured neurones. Cell Biol. Toxicol. 20, 361–374 (2004). source
• Not checked yetcites [198] Tong, M. et al. Acetaldehyde-mediated neurotoxicity: relevance to fetal alcohol spectrum disorders. Oxid. Med. Cell. Longev. 2011, e213286 (2011). source

In the paper

“Excessive alcohol exposure increases oxidative stress and the levels of reactive acetaldehyde and lipid aldehydes with a simultaneous decrease in defensive molecules and detoxification enzymes, including GSH and ALDH253,172,177.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged

  “These changes subsequently lead to the accumulation of acetaldehyde adducts and possibly AGEs in the brain, which has a much lower detoxification capacity than the liver, as previously mentioned102.”

What the sources say

• Not checked yetcites [53] Song, B. J. et al. Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications. Redox Biol. 3, 109–123 (2014). source
• Not checked yetcites [172] Doorn, J. A., Hurley, T. D. & Petersen, D. R. Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem. Res. Toxicol. 19, 102–110 (2006). source
• Not checked yetcites [177] Hartley, D. P. & Petersen, D. R. Co-metabolism of ethanol, ethanol-derived acetaldehyde, and 4-hydroxynonenal in isolated rat hepatocytes. Alcohol. Clin. Exp. Res. 21, 298–304 (1997). source
• Not checked yetcites [102] de la Monte, S. M. & Kril, J. J. Human alcohol-related neuropathology. Acta Neuropathol. 127, 71–90 (2014). source

In the paper

“Moreover, ethanol ingestion also upregulates RAGE expression in the orbitofrontal cortex and increases the levels of oxidative stress, HMGB1, TLR-4, neuroimmune markers, and proinflammatory cytokines in the brain201.”

What the sources say

• Not checked yetcites [201] Vetreno, R. P., Qin, L. & Crews, F. T. Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking. Neurobiol. Dis. 59, 52–62 (2013). source

In the paper

“Additionally, the aggregation of these AA-protein adducts can enhance neuronal damage and degeneration in different brain regions190,196.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · hedged

  “These findings suggest a critical role for AA-protein adducts in promoting brain damage and pathophysiology associated with chronic alcohol consumption.”

What the sources say

• Not checked yetcites [190] Nakamura, K. et al. Acetaldehyde adducts in the brain of alcoholics. Arch. Toxicol. 77, 591–593 (2003). source
• Not checked yetcites [196] Iwahashi, K. et al. [Acetaldehyde adducts in the cerebral cortex of ethanol-fed mice]. Nihon Arukoru Yakubutsu Igakkai zasshi 32, 489–494 (1997)..

In the paper

“Additionally, chronic exposure to alcohol enhances RAGE expression, ROS generation, nuclear factor erythroid 2–related factor 2 (Nrf2), TLR-4, glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba1), and lipid peroxidation, resulting in neuroinflammation, neuronal apoptosis, and memory impairment202.”

What the sources say

• Not checked yetcites [202] Ikram, M. et al. Natural dietary supplementation of curcumin protects mice brains against ethanol-induced oxidative stress-mediated neurodegeneration and memory impairment via Nrf2/TLR4/RAGE signaling. Nutrients 11, E1082 (2019). source

In the paper

“AA-protein adducts are widely present in the brains of alcohol-exposed rodents or people with alcohol use disorder (AUD)189–192.”

• Also stated in: § AGE–alcohol–adduct formations (Fig. 1) · plain

  “AA-protein adducts are also formed with cytosolic proteins, including tubulins, known as AA-tubulin adducts, resulting in microtubule malformation and the cytoskeletal dysfunction of nerve cells193,194.”

What the sources say

• Not checked yetcites [189] Rintala, J. et al. Evidence of acetaldehyde-protein adduct formation in rat brain after lifelong consumption of ethanol. Alcohol Alcohol. 35, 458–463 (2000). source
• Not checked yetcites [190] Nakamura, K. et al. Acetaldehyde adducts in the brain of alcoholics. Arch. Toxicol. 77, 591–593 (2003). source
• Not checked yetcites [191] Upadhya, S. C. & Ravindranath, V. Detection and localization of protein-acetaldehyde adducts in rat brain after chronic ethanol treatment. Alcohol. Clin. Exp. Res. 26, 856–863 (2002). source
• Not checked yetcites [192] Heymann, H. M., Gardner, A. M. & Gross, E. R. Aldehyde-induced DNA and protein adducts as biomarker tools for alcohol use disorder. Trends Mol. Med 24, 144–155 (2018). source
• Not checked yetcites [193] Tuma, D. J., Smith, S. L. & Sorrell, M. F. Acetaldehyde and microtubules. Ann. N. Y. Acad. Sci. 625, 786–792 (1991). source
• Not checked yetcites [194] Smith, S. L., Jennett, R. B., Sorrell, M. F. & Tuma, D. J. Acetaldehyde substoichiometrically inhibits bovine neurotubulin polymerization. J. Clin. Investig. 84, 337–341 (1989). source